Process for producing quinolonecarboxylic acids and intermediates thereof

ABSTRACT

This invention relates to methods for the efficient production of quinolonecarboxylic acid based synthetic antibacterial agents which are expected for applications such as excellent medicaments and agricultural chemicals and to intermediate compounds to be used therein. According to the present invention, an amine substituent as the 7-position substituent of the quinolonecarboxylic acid derivative can be efficiently introduced.

TECHNICAL FIELD

This invention relates to methods for the efficient production ofquinolonecarboxylic acid synthetic antibacterial agents which areexpected for applications such as excellent medicaments and agriculturalchemicals and to intermediate compounds to be used therein.

BACKGROUND ART

Among quinolone synthetic antibacterial agents useful as antibacterialagents, 5-amino-8-methylquinolonecarboxylic acid derivatives are knownto have excellent characteristics. As shown below,

synthesis of such quinolone derivatives is carried out by allowing acompound of formula (1) to react with a basic substituent compound (R—H;which means a compound capable of introducing a basic substituent by asubstitution reaction). For example, a method of the following formula:

is known, in which a 5-amino-8-methylquinolonecarboxylic acid BF₂chelate [a compound of the formula (1) wherein R³=NH₂, R⁴=Me and Y=BF₂]is allowed to react with a basic substituent compound in an appropriatesolvent in the presence of an appropriate base.

That is, a method in which(S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (or itshydrochloride) is allowed to undergo the reaction at 30° C. for 3 to 4days in dimethyl sulfoxide in the presence of N,N-diisopropylamine andthen purified, and the thus obtained crystals are allowed to undergo thereaction by heating in a mixed solvent of methanol-1,2-dichloroethane inthe presence of triethylamine and then purified, thereby obtaining5-amino-7-[(S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (JP-A-7-309864 and JP-A-8-198819; the term “JP-A” as used hereinmeans an “unexamined published Japanese patent application”) However,this is not an industrially satisfactory method because of the lowproduct yield of approximately from 10 to 30%.

Also known is a method in which 5-amino-8-methylquinolonecarboxylic acid[a compound of the formula (1) wherein R³=NH₂, R⁴=Me and Y=H] and abasic substituent compound are heated in an appropriate solvent in thepresence of an appropriate base. That is, a method in which they arestirred and heated at about 100° C. for 87 hours in dimethyl sulfoxidein the presence of triethylamine and then treated, and the thus obtainedcrystals are purified after carrying out deprotection of amino group inthe usual way, thereby obtaining5-amino-7-[(3S,4S)-3-amino-4-ethyl-1-pyrrolidinyl]-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (JP-A-8-259561) (the following formula):

or a method (the following formula):

in which5-amino-7-[(S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid is obtained (Chem. Pharm. Bull., 44, 1376 (1996)).

However, yields of the final products by these methods are still low,namely 38% and 56% respectively, so that, though the yields are slightlyimproved in comparison with the foregoing method, they are notindustrially satisfactory methods.

Thus, the previous methods for the production of5-amino-8-methylquinolonecarboxylic acid derivatives were notsatisfactory as an industrial production method.

Under such a situation, the present inventors have examined the reasonof low yield of the previous reaction of a boron chelate compound ofY=—B(R⁵)₂ in the compound of formula (1) of the invention[(5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid-O³,O⁴)difluoroboron] with a basic substituent compound.

As a result, it was found that the boron chelate compound easily causesde-chelation on heating. Thus, it was confirmed that de-chelation in theboron chelate quinolone compound preferentially proceeds rather thanreacting with a basic substituent compound when the reaction temperatureis increased for the purpose of accelerating the reaction (e.g., even bya heating at 30 to 40° C.), while substitution reaction of the compoundformed by this de-chelation with the basic substituent compound hardlyproceeds at this temperature.

In addition, an open system reaction is carried out under a hightemperature (110° C.) condition in the case of the substitution reactionof a carboxylic acid type quinolone compound [a compound in which the3-position carboxyl group is not modified, such as5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid itself] with a pyrrolidine derivative. It was found that, sincedecomposition reaction of the carboxylic acid quinolone compound itselfcompetitively occurs simultaneously with the substitution reaction bythis method, the reaction becomes complex in addition to coloring of thereaction solution. That is, the inventors have considered that yield ofthe substitution product is reduced due to decomposition of the materialcompound, and further reduction of the yield occurs because of thedifficulty in purifying the final product of interest due to the complexreaction and coloring.

By the way, it is known that the substitution reaction of aromatichalogen compounds with amines sharply progresses when the reaction iscarried out in an appropriate solvent under a super-high pressure (cf.Heterocycles, 27,319 (1988); Chem. Lett., 1187 (1987); Synthesis, 1147(1990); Tetrahedron Lett., 3923 (1990); Bull. Chem. Soc. Jpn., 64, 42(1991)). However, such a substitution reaction under a high pressure ismainly a reaction with a monocyclic halogen compound such as benzene,pyrimidine, pyrazine or thiazole, and only a few examples such asbenzoxazole and benzothiazole are known as bicyclic halogen compoundsbut there are no reports on 4-quinolone compounds.

An object of the invention is to provide a method for the efficientproduction of quinolone compounds having excellent antibacterialactivity, pharmacokinetics and safety, particularly a 7-substituted5-amino-8-methylquinolonecarboxylic acid derivative.

DISCLOSURE OF THE INVENTION

As a result of intensive studies, the present inventors have found thata 5-amino-8-methylquinolonecarboxylic acid derivative can be efficientlyprovided through inhibition of the decomposition reaction of thequinolone material compound, by carrying out the substitution reactionof a5-amino-1-substituted-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid with a basic substituent compound under a high pressure, therebyaccomplishing the invention.

The inventors have further found that the substitution reaction with abasic substituent compound quickly proceeds in-the case of a compound inwhich the 5-position amino group is acylated, and excellent effects areexerted particularly by the reaction under a pressurized condition, thusresulting in the accomplishment of the invention.

Accordingly, the invention relates to a method for producing a compoundrepresented by formula (2):

(wherein R¹, R², R³, R⁴, R, X¹ and Y are as defined in the following)which comprises allowing a compound represented by formula (1):

[wherein R¹ represents an alkyl group having from 1 to 6 carbon atoms,an alkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl grouphaving from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6carbon atoms which may have a substituent, an aryl group which may havea substituent, a heteroaryl group which may have a substituent, analkoxy group having from 1 to 6 carbon atoms or an alkylamino grouphaving from 1 to 6 carbon atoms,

R² represents a hydrogen atom or an alkylthio group having from 1 to 6carbon atoms,

wherein R² and R¹ may be combined to form a cyclic structure togetherwith the carbon atom and nitrogen atom, to which they are bonded, andthis ring may contain a sulfur atom as a constituting atom and mayfurther have an alkyl group having from 1 to 6 carbon atoms as asubstituent,

R³ represents a hydrogen atom, an amino group, a thiol group, ahalogenomethyl group, an alkyl group having from 1 to 6 carbon atoms, analkenyl group having from 2 to 6 carbon atoms, an alkynyl group havingfrom 2 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbonatoms,

wherein the amino group may have one or more substituents selected fromthe group consisting of a formyl group, an alkyl group having from 1 to6 carbon atoms and an acyl group having from 2 to 5 carbon atoms,

R⁴ represents a hydrogen atom, an amino group, a halogen atom, a cyanogroup, a halogenomethyl group, a halogenomethoxy group, an alkyl grouphaving from 1 to 6 carbon atoms, an alkenyl group having from 2 to 6carbon atoms, an alkynyl group having from 2 to 6 carbon atoms or analkoxy group having from 1 to 6 carbon atoms,

wherein the amino group may have one or more substituents selected fromthe group consisting of a formyl group, an alkyl group having from 1 to6 carbon atoms and an acyl group having from 2 to 5 carbon atoms, and

R⁴ and R¹ maybe combined to form a cyclic structure together with thecarbon atom and nitrogen atom, to which they are bonded, and this ringmay contain an oxygen atom, a nitrogen atom or a sulfur atom as aconstituting atom and may further have an alkyl group having from 1 to 6carbon atoms as a substituent,

X¹ represents a hydrogen atom or a halogen atom,

X² represents a halogen atom, and

Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, apivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, adimethylaminoethyl group, a 5-indanyl group, a phthalidynyl group, a5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group,an alkyl group having from 1 to 6 carbon atoms, an alkoxymethyl grouphaving from 2 to 7 carbon atoms, a phenylalkyl group composed of analkylene group having from 1 to 6 carbon atoms and a phenyl group, or agroup of the following formula:

—B(R⁵)₂

(wherein R⁵ represents a fluorine atom or an acyloxy group having from 2to 7 carbon atoms)]

to react with a nitrogen-containing basic compound represented by thefollowing formula:

R—H

(wherein R represents a nitrogen-containing basic substituent in which anitrogen atom is the binding position), under a pressurized condition inthe presence, if necessary, of a base.

The invention also relates to the above production method, wherein thecompound of formula (I) is a compound represented by formula (A):

[wherein X¹ is a hydrogen atom or a halogen atom, X² is a halogen atom,X³ is a hydrogen atom or a halogen atom, R¹⁶ is a hydrogen atom or anacyl group, R¹⁷ is an acyl group, and R¹⁸ is a hydrogen atom, an alkylgroup having from 1 to 6 carbon atoms or a boron-containing substituentgroup represented by the following formula:

—B(R⁵)₂

(wherein R⁵ is a halogen atom or an acyloxy group)].

It also relates to the above production method wherein R⁵ is a halogenatom or an alkylcarbonyloxy group;

to the above production method wherein R⁵ is a fluorine atom or anacetyloxy group;

to the above production method wherein the nitrogen-containing basiccompound (R—H) is a compound represented by a formula (B):

[wherein each of R¹⁹ and R²⁰ is independently a hydrogen atom, a loweralkyl group or an amino-substituted cyclopropyl group (this amino groupmay have a substituent or a protective group), or R¹⁹ and R²⁰ may becombined into a group represented by the following formula:

—(CH₂)₂—

and form a spiro cyclic structure together with the pyrrolidine ring,and R²¹ is a halogen atom or an amino group which may have a substituentor a protective group];

to the above production method wherein R¹⁹ and R²⁰ are a grouprepresented by the following formula:

—(CH₂)₂—

and R²¹ is an amino group which may have a substituent or a protectivegroup;

to the above production method wherein the amino group is an amino groupof (S)-configuration;

to the above production method wherein R¹⁹ is a hydrogen atom, R²⁰ is anamino-substituted cyclopropyl group (this amino group may have asubstituent or a protective group) and R²¹ is a halogen atom;

to the above production method wherein R²¹ is a fluorine atom; to theabove production method wherein R²⁰ and R²¹ are in cis-form; and to theabove production method wherein R²⁰ is (R)-configuration and R²¹ is(S)-configuration.

The invention also relates to a compound represented by formula (A):

[wherein X¹ represents a hydrogen atom or a halogen atom, X² representsa halogen atom, X³ represents a hydrogen atom or a halogen atom, R¹⁶represents a hydrogen atom or an acyl group, R¹⁷ represents an acylgroup, and R¹⁸ represents a hydrogen atom, an alkyl group having from 1to 6 carbon atoms or a boron-containing substituent represented by thefollowing formula:

—B(R⁵)₂

(wherein R⁵ represents a halogen atom or an acyloxy group)], and furtherrelates to the following related compounds.

The above compound wherein R¹⁶ is a hydrogen atom and R¹⁷ is an acylgroup;

each of the above compounds wherein R¹⁷ is an acetyl group;

each of the above compounds wherein X¹ and X² are a fluorine atoms;

each of the above compounds wherein R¹⁸ is a hydrogen atom; a compoundrepresented by formula (C-1):

[wherein X¹ represents a hydrogen atom or a halogen atom, X³ representsa hydrogen atom or a halogen atom, each of R¹⁹ and R²⁰ independentlyrepresents a hydrogen atom, a lower alkyl group or an amino-substitutedcyclopropyl group (this amino group may have a substituent or aprotective group), or R¹⁹ and R²⁰ maybe combined into a grouprepresented by the following formula

—(CH₂)₂—

and form a spiro cyclic structure together with the pyrrolidine ring,and R²¹ represents a halogen atom or an amino group which may have asubstituent or a protective group];

the above compound wherein R¹⁹ and R²⁰ are a group represented by thefollowing formula:

—(CH₂)₂—

and R²¹ is an amino group which may have a substituent or a protectivegroup;

the above compound wherein the amino group is an amino group of(S)-configuration;

the above compound wherein R¹⁹ is a hydrogen atom, R²⁰ is anamino-substituted cyclopropyl group (this amino group may have asubstituent or a protective group) and R²¹ is a halogen atom;

the above compound wherein R²¹ is a fluorine atom;

the above compound wherein R²⁰ and R²¹ are in cis-form;

the above compound wherein R²⁰ is (R)-configuration and R²¹ is(S)-configuration;

a compound represented by formula (C-2):

[wherein X¹ represents a hydrogen atom or a halogen atom, X³ representsa hydrogen atom or a halogen atom, R¹⁶ represents a hydrogen atom or anacyl group, R¹⁷ represents an acyl group, R¹⁸ represents a hydrogenatom, an alkyl group having from 1 to 6 carbon atoms or aboron-containing substituent represented by the following formula:

—B(R⁵)₂

(wherein R⁵ represents a halogen atom or an acyloxy group), each of R²²and R²³ independently represents a hydrogen atom, a lower alkyl group oran amino-substituted cyclopropyl group (this amino group may have asubstituent), or R²² and R²³ may be combined into a group represented bythe following formula:

—(CH₂)₂—

and form a spiro cyclic structure together with the pyrrolidine ring,and R²³ represents a halogen atom or an amino group which may have asubstituent];

the above compound wherein R²² and R²³ are a group represented by thefollowing formula:

—(CH₂)₂—

and R²⁴ is an amino group which may have a substituent; the abovecompound wherein the amino group is an amino group of (S)-configuration;

the above compound wherein R²² is a hydrogen atom, R²³ is anamino-substituted cyclopropyl group (this amino group may have asubstituent) and R²⁴ is a halogen atom;

the above compound wherein R²⁴ is a fluorine atom;

the above compound wherein R²³ and R²⁴ are in cis-form;

the above compound wherein R²³ is (R)-configuration and R²⁴ is(S)-configuration;

the above compound wherein R¹⁶ is a hydrogen atom and R¹⁷ is an acylgroup;

the above compound wherein R¹⁷ is an acetyl group;

each of the above compounds wherein X¹ and X³ are fluorine atoms; and

each of the above compounds wherein R¹⁸ is a hydrogen atom.

The production method of the invention is characterized in that thefollowing substitution reaction is carried out under a pressurizedcondition:

(wherein R¹, R², R³, R⁴, R⁵, R⁶, R, X¹, X² and Y are as defined in theforegoing).

Firstly, substituent groups of the compound represented by the formula(1) or (2) are described.

The substituent R¹ is an alkyl group having from 1 to 6 carbon atoms, analkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl grouphaving from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6carbon atoms having a substituent, an aryl group which may have asubstituent, a heteroaryl group which may have a substituent, an alkoxygroup having from 1 to 6 carbon atoms or an alkylamino group having from1 to 6 carbon atoms.

In this case, an ethyl group is particularly preferable as the alkylgroup having from 1 to 6 carbon atoms. A vinyl group or a 1-isopropenylgroup is preferable as the alkenyl group having from 2 to 6 carbonatoms. A 2-fluoroethyl group is preferable as the halogenoalkyl grouphaving from 1 to 6 carbon atoms. A halogen atom is preferable as thesubstituent group of the cyclic alkyl group having a substituent, and afluorine atom is particularly preferable as the halogen atom.

Examples of the aryl group which may have a substituent include phenylgroups which may have from 1 to 3 substituents selected from the groupconsisting, for example, of halogen atoms such as a fluorine atom, achlorine atom and a bromine atom, a hydroxyl group, an amino group, anitro group, an alkyl group having from 1 to 6 carbon atoms and analkoxy group having from 1 to 6 carbon atoms, of which a phenyl group, a2-fluorophenyl group, a 4-fluorophenyl group, a 2,4-difluorophenylgroup, a 2-fluoro-4-hydroxyphenyl group, a 3-amino-4,6-difluorophenylgroup and a 4,6-difluoro-3-methylaminophenyl group are preferable.

The heteroaryl group is a substituent derived from a five-membered orsix-membered aromatic heterocyclic compound containing one or morehetero-atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom. As examples of the heteroaryl group of substituent R¹, a pyridylgroup and a pyrimidyl group can be cited. An alkyl group and a halogenatom, for example, are preferable as the substituents on these rings. A6-amino-3,5-difluoro-2-pyridyl group is particularly preferable.

A methoxy group is preferable as the alkoxy group having from 1 to 6carbon atoms. A methylamino group is preferable as the alkylamino grouphaving from 1 to 6 carbon atoms.

As the substituent R¹, a halogenocycloalkyl group is preferred, and a2-halogenocyclopropyl group is more preferred. As the halogen atom, afluorine atom is preferable.

The substituent R² is a hydrogen atom or an alkylthio group having from1 to 6 carbon atoms, or R² and R¹ may be combined to form a hydrocarboncyclic structure together with the carbon atom and nitrogen atom, towhich they are bonded. The thus formed ring may contain a sulfur atom asa constituting atom, and this ring may further have an alkyl grouphaving from 1 to 6 carbon atoms as a substituent. The ring to be formedmay have a size of from four-membered ring to six-membered ring, andthis ring may be in a saturated, partially saturated or unsaturatedform. The following can be cited as the condensed ring structure formedin this manner.

The substituent X¹ is a hydrogen atom or a halogen atom, and a fluorineatom is preferable when it is a halogen atom. Among them, a fluorineatom or a hydrogen atom is preferable as the substituent.

The substituent R³ is a hydrogen atom, an amino group, a thiol group, ahalogenomethyl group, an alkyl group having from 1 to 6 carbon atoms, analkenyl group having from 2 to 6 carbon atoms, an alkynyl group havingfrom 2 to 6 carbon atoms or an alkoxy group having from 1 to 6 carbonatoms, wherein the amino group may have one or more substituentsselected from the group consisting of a formyl group, an alkyl grouphaving from 1 to 6 carbon atoms and an acyl group having from 2 to 5carbon atoms.

The alkyl group is a straight chain or branched chain group having from1 to 6 carbon atoms, preferably a methyl group, an ethyl group, an-propyl group or an isopropyl group. The alkenyl group is a straightchain or branched chain group having from 2 to 6 carbon atoms,preferably a vinyl group. The alkynyl group is a straight chain orbranched chain group having from 2 to 6 carbon atoms, preferably anethynyl group. As the halogen of halogenomethyl group, a fluorine atomis particularly preferable, and its number is from 1 to 3. As the alkoxygroup, it may have from 1 to 6 carbon atoms, and an methoxy group ispreferable.

The substituent R³ is preferably a hydrogen atom, an alkyl group or anamino group, of which a methyl group or an unsubstituted amino group ispreferable.

When the substituent R³ is an amino group or a thiol group, it may beprotected with a usually used protective group.

Examples of the protective group include a (substituted) alkoxycarbonylgroup such as a tert-butoxycarbonyl group or a2,2,2-trichloroethoxycarbonyl group; a (substituted) aralkyloxycarbonylgroup such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonylgroup or a p-nitrobenzyloxycarbonyl group; a (substituted) acyl groupsuch as an acetyl group, a methoxyacetyl group, a trifluoroacetyl group,a chloroacetyl group, a pivaloyl group, a formyl group or a benzoylgroup; a (substituted) alkyl group or a (substituted) aralkyl group suchas a tert-butyl group, a benzyl group, a p-nitrobenzyl group, ap-methoxybenzyl group or a triphenylmethyl group; (substituted) etherssuch as a methoxymethyl group, a tert-butoxymethyl group, atetrahydropyranyl group and a 2,2,2-trichloroethoxymethyl group; and(alkyl and/or aralkyl)-substituted silyl groups such as a trimethylsilylgroup, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group,a tribenzylsilyl group and a tert-butyldiphenylsilyl group. Compoundshaving certain substituents protected with these substituents areparticularly preferable as production intermediates (the term“(substituted)” as used herein means that it may have a substituent).

R⁴ is a hydrogen atom, an amino group, a halogen atom, a cyano group, ahalogenomethyl group, a halogenomethoxy group, an alkyl group havingfrom 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbonatoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxygroup having from 1 to 6 carbon atoms,

wherein the amino group may have one or more substituents selected fromthe group consisting of a formyl group, an alkyl group having from 1 to6 carbon atoms and an acyl group having from 2 to 5 carbon atoms.

The alkyl group is a straight chain or branched chain group having from1 to 6 carbon atoms, preferably a methyl group, an ethyl group, an-propyl group or an isopropyl group. The alkenyl group is a straightchain or branched chain group having from 2 to 6 carbon atoms,preferably a vinyl group. The alkynyl group is a straight chain orbranched chain group having from 2 to 6 carbon atoms, preferably anethynyl group. As the halogen of halogenomethyl group, a fluorine atomis particularly preferable, and its number may be from 1 to 3. As thealkoxy group, it may have from 1 to 6 carbon atoms, and a methoxy groupis preferable. As the halogen of halogenomethoxy group, a fluorine atomis particularly preferable, and its number may be from 1 to 3.

Among these substituents, alkyl groups or alkoxy groups are preferably.More preferred are a methyl group and an ethyl group.

In addition, this R⁴ and the R¹ described in the foregoing may becombined to form a hydrocarbon cyclic structure together with the carbonatom and nitrogen atom, to which they are bonded, (the ring has a sizeof from four-membered ring to seven-membered ring, which may be in asaturated, partially saturated or unsaturated form), and the thus formedring may contain an oxygen atom, a nitrogen atom or a sulfur atom as aconstituting atom and may further have an alkyl group having from 1 to 6carbon atoms as a substituent. The following structures can beexemplified as the condensed ring structure formed in this manner.

Among these condensed ring systems,2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1.4]benzoxazine-6-carboxy-10-ylgroup, particularly its 3-position (S)-methyl compound, is preferred.

Preferred as the combination of R³ and R⁴ is a case in which R³ is anamino group, a hydrogen atom or an alkyl group having from 1 to 6 carbonatoms and R⁴ is an alkyl group having from 1 to 6 carbon atoms, analkoxy group having from 1 to 6 carbon atoms, a halogenomethoxy group ora hydrogen atom.

More preferred combination is a case in which R³ is an amino group, ahydrogen atom or a methyl group and R⁴ is a methyl group, a methoxygroup, a difluoromethoxy group or a hydrogen atom.

Particularly preferred combination is a case in which R³ is an aminogroup, a hydrogen atom or a methyl group and R⁴ is a methyl group or amethoxy group.

For these R³ and R⁴, a fluorine atom is preferable as X¹.

When each of X¹ and X² is a halogen atom, a fluorine atom isparticularly preferable as X¹.

X² is a substituent which serves as a leaving group such as a fluorineatom, a chlorine atom, a bromine atom, a substituted or unsubstitutedphenylsulfonyl group or a substituted or unsubstituted alkylsulfonylgroup having from 1 to 3 carbon atoms.

Y is a group which constitutes a carboxyl group or an carboxy ester.When it is a carboxy ester, the compound is useful as a synthesisintermediate or a prodrug. For example, alkyl esters, benzyl esters,alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful assynthesis intermediates.

Also, the ester to be used as a prodrug is an ester which is easilyhydrolyzed in vivo and thereby forms a free carboxylic acid, and itsexamples include oxoalkyl esters such as acetoxymethyl ester,pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester,dimethylaminoethyl ester, 5-indanyl ester, phthalidynyl ester,5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester and 3-acetoxy-2-oxobutylester.

In addition, when Y is a group having a structure represented by thefollowing formula:

—B(R⁵)₂,

R⁵ is a fluorine atom or an acyloxy group having from 2 to 7 carbonatoms. The acyl moiety of the acyloxy group may be either an aliphaticacyl group or an aromatic acyl group. The aliphatic acyl group is anyalkylcarbonyl group. A benzoyl group can be cited as the aromatic acylgroup. As the acyloxy group of R⁵, the use of acetyloxy group is mostconvenient.

The halogenocyclopropyl group of R¹ is described. As the halogen atom tobe substituted, a fluorine atom and a chlorine atom can be exemplified,and a fluorine atom is particularly preferable.

As the stereochemical environment of this moiety, regarding thecyclopropane ring, it is particularly preferable that the halogen atomand pyridone-carboxylic acid moiety are in cis-form. More preferred is a(1R, 2S)-2-fluorocyclopropyl group.

So-called antipode isomers exist merely in this cis-2-halogenopropylmoiety of R¹, and strong antibacterial activity and high safety werefound in each of them.

On the other hand, the nitrogen-containing basic compound is a compoundcapable of introducing a basic substituent by a substitution reaction,represented by formula R—H (wherein R is a nitrogen-containing basicsubstituent in which a nitrogen atom is the binding region).

A compound (A) can be exemplified as a preferred example of the compoundof formula (1):

[In this formula, X¹ is a hydrogen atom or a halogen atom, X² is ahalogen atom, X³ is a hydrogen atom or a halogen atom, R¹⁶ is a hydrogenatom or an acyl group, R¹⁷ is an acyl group, and R¹⁸ is a hydrogen atom,an alkyl group having from 1 to 6 carbon atoms or a boron-containingsubstituent represented by the following formula

—B(R⁵)₂

(wherein R⁵ is a halogen atom or an acyloxy group).]

The substituent R¹⁶ is a hydrogen atom or an acyl group. As the acylgroup, it may be either aliphatic or aromatic and may further have ansubstituent group. Examples of such a substituent include a lower alkylgroup and a halogen atom. Examples of the alkyl group include a methylgroup, an ethyl group and a propyl group, and examples of the halogenatom include a fluorine atom, a chlorine atom and a bromine atom.

Examples of the acyl group include a formyl group, an acetyl group, apropanoyl group, a butyroyl group, a benzoyl group, a fluoroacetylgroup, a didluoroacetyl group, a trifluoroacetyl group, a chloroacetylgroup, a dichloroacetyl group and a trichloroacetyl group. Among them,an acetyl group or a substituted acetyl group is preferred, and anacetyl group is most preferred.

R¹⁷ is an acyl group, and this acyl group can be regarded as the samegroup of R¹⁶. When R¹⁶ and R¹⁷ are simultaneously acyl groups, they maybe the same or different from each other.

R¹⁸ is a hydrogen atom, a lower alkyl group or a boron-containingsubstituent represented by the following formula:

—B(R⁵)₂

(wherein R⁵ is a halogen atom or an acyloxy group).

When R⁵ is a lower alkyl group, it may be either a straight chain or abrunched chain group having from 1 to 6 carbon atoms and may furthercontain a cyclic moiety. Illustrative examples of the alkyl groupinclude a methyl group, an ethyl group and an isopropyl group.

When R¹⁸ is a boron-containing substituent having the above structure,R⁵ is preferably a halogen atom or an acyloxy group. As the halogenatom, a fluorine atom is preferred. The acyl group may be any one of theacyl groups exemplified in R¹⁶ and R¹⁷. An acetyl group or a substitutedacetyl group is preferable as the acyl group. More preferred is anacetyl group. As the boron-containing substituent, a dihalogenoborongroup is preferable, and a difluoroboron group is particularlypreferable.

Illustrative examples of the mother nucleus of quinolone compounds areshown below:

The basic substituent compound (R—H) to be reacted with these compoundsis described.

The compound R—H is represented for example by a formula (3):

which is characterized in that R⁶ and R⁷ may be the same or differentfrom each other and each represents an optional substituent selectedfrom an alkyl group having from 1 to 6 carbon atoms which may besubstituted by an optional substituent selected from the group (halogen,C₁₋₆ alkyl group and C₁₋₆ alkoxy group), an alkyl group having from 1 to6 carbon atoms, an aryl group having from 6 to 10 carbon atoms, anaralkyl group having from 7 to 12 carbon atoms, an acyl group havingfrom 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 6 carbonatoms and a hydrogen atom, wherein the cycloalkyl group, aryl group andaralkyl group may become a heterocycle containing one or morehetero-atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom.

Its illustrative examples include amine compounds such as ethylamine,butylamine, diethylamine, isopropylamine, tert-butylamine,diisopropylamine, benzylamine, benzylmethylamine, dibenzylamine,cyclopropylamine, cyclohexylamine and aniline, and compounds in whichthese unsubstituted compounds are substituted with a substituentoptionally selected from the above groups.

Alternatively, R⁶ and R⁷ may form a ring together with the nitrogenatom, to which they are bonded, and the formed ring is a monocyclic,bicyclic or tricyclic nitrogen-containing heterocyclic substituent,

the heterocyclic substituent may be either in saturated or unsaturatedform, may further contain one or more hetero-atoms selected from anitrogen atom, an oxygen atom and a sulfur atom and may have a bicyclostructure or a spiro cyclic structure,

and the heterocyclic substituent has a characteristic in that it may besubstituted by one or more optional substituents selected from groups(1), (2) and (3).

Substituent group (1); a C₆₋₁₀ aryl group, a heteroaryl group(five-membered ring or six-membered ring which may contain from 1 to 4hetero-atoms optionally selected from N, O and S), a C₇₋₁₂ aralkyl groupand C₆₋₁₀ heteroaralkyl group (which may contain from 1 to 4hetero-atoms optionally selected from N, O and S).

Substituent group (2); an amino group, a C₁₋₆ alkyl group, a C₁₋₆alkylamino group, a C₁₋₆ alkylthio group, a C₁₋₆ halogenoalkyl group anda C₁₆ aminoalkyl group.

Substituent group (3); a halogen atom, a hydroxyl group, a carbamoylgroup and a C₁₋₆ alkoxyl group.

Regarding the substituent group (1) which may have a substituent,preferred is at least one optional substituent selected from an alkylgroup, an alkoxy group, an alkylthio group, an alkoxycarbonyl group andan acyl group, which are substituted with at least one optionalsubstituent selected from the group A (an amino group, a halogen atom, ahydroxyl group, a carbamoyl group, a C₂₋₆ alkyl group, a C₂₋₆ alkoxygroup, a C₂₋₆ alkylamino group, a C₂₋₆ alkylthio group, a thiol group, anitro group, a cyano group, a carboxyl group, a phenyl group, a C₂₋₆alkoxycarbonyl group and a C₂₋₅ acyl group) and the group B (a halogenatom, a hydroxyl group, a C₁₋₆ alkoxy group and a C₁₋₆ alkylthio group).

Regarding the substituent groups (2) and (3) which may have asubstituent, preferred is at least one substituent selected from a C₁₋₆alkyl group, a C₁₋₆ alkoxy group, a C₆₋₁₀ aryl group and a heteroarylgroup (five-membered ring or six-membered ring which may contain from 1to 4 hetero-atoms optionally selected from N, O and S).

The alkyl group moiety of the substituent group (2) may have a cyclicstructure.

The amino group of the substituent group A and the amino group and aminogroup moiety of the substituent group (2) may have, as 1 or 2substituents, a C₁₋₆ alkyl group (this alkyl group may have a cyclicstructure) which may have one or more substituents selected from thegroup C (a hydroxyl group, a halogen atom, a C₁₋₆ alkylthio group and aC₁₋₆ alkoxy group) (when the number of alkyl group is 2, they may be thesame or different from each other), and may be protected with aprotective group.

More preferred is a monocyclic, bicyclic or tricyclicnitrogen-containing heterocyclic substituent in which the nitrogen atomexisting in the molecule is the binding position, which is characterizedin that

the nitrogen-containing heterocyclic substituent is in saturated orunsaturated form and may further contain one or more hetero-atomsselected from a nitrogen atom, an oxygen atom and a sulfur atom,

the nitrogen-containing heterocyclic substituent may also have one ormore substituent selected from the group consisting of a halogen atom,an amino group, a hydroxyl group, an alkyl group having from 1 to 6carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms, anaminoalkyl group having from 1 to 6 carbon atoms and an alkylamino groupwhich has 1 or 2 alkyl groups having from 1 to 6 carbon atoms,

the alkyl group moiety of these alkyl group, halogenoalkyl group,aminoalkyl group and alkylamino group may have a cyclic structure andmay have one or more substituents selected from the group consisting ofa halogen atom, an alkyl group having from 1 to 6 carbon atoms and analkoxy group having from 1 to 6 carbon atoms, and

the amino group and the amino group moiety of amino alkyl group andalkylamino group may be protected with a protective group.

Regarding the cyclic structure which is formed when “the alkyl groupmoiety has a cyclic structure”, its examples include a case in which itbinds to the nitrogen-containing heterocyclic substituent by forming aspiro cyclic structure, a case in which it becomes a cycloalkylenegroup, and one of its bonds binds to the nitrogen-containingheterocyclic substituent and a case in which an alkyl group binds to thenitrogen-containing heterocyclic substituent, and a spiro cyclicstructure is formed on the chain or forms a cycloalkyl structure.

The following structures can be exemplified as the substituent R:

[In the above formulae, each of R¹² and R¹³ independently represents ahydrogen atom, an alkyl group having from 1 to 6 carbon atoms, a cyclicalkyl group having from 3 to 6 carbon atoms, a halogenoalkyl grouphaving from 1 to 6 carbon atoms, a hydroxyalkyl group having from 1 to 6carbon atoms or a protective group of amino group, or R¹² and R¹³ may becombined into a polyalkylene chain having from 2 to 6 carbon atoms andform a cyclic structure by including the nitrogen atom, to which R¹² andR¹³ are bonded,

R¹⁴ and R¹⁵ independently represents a hydrogen atom, an alkyl grouphaving from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6carbon atoms, a halogenoalkyl group having from 1 to 6 carbon atoms or ahydroxyalkyl group having from 1 to 6 carbon atoms,

or R¹⁴ and R¹⁵ may be combined into a polyalkylene chain having from 2to 6 carbon atoms and form a cyclic structure by including the carbonatom, to which R¹⁴ and R¹⁵ are bonded, R″ represents a hydrogen atom, ahalogen atom, a hydroxyl group, an alkyl group having from 1 to 6 carbonatoms, a cyclic alkyl group having from 3 to 6 carbon atoms, ahalogenoalkyl group having from 1 to 6 carbon atoms, a hydroxyalkylgroup having from 1 to 6 carbon atoms or a polyalkylene group havingfrom 2 to 6 carbon atoms (in this case, a cyclic structure is formed byincluding the atom, to which R″ is bonded), and

each of m and n independently represents an integer of from 1 to 4.

Examples of the protective group of amino group include a (substituted)alkoxycarbonyl group such as a tert-butoxycarbonyl group or a2,2,2-trichloroethoxycarbonyl group; a (substituted) aralkyloxycarbonylgroup such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonylgroup or a p-nitrobenzyloxycarbonyl group; a (substituted) acyl groupsuch as an acetyl group, a methoxyacetyl group, a trifluoroacetyl group,a chloroacetyl group, a pivaloyl group, a formyl group or a benzoylgroup; a (substituted) alkyl group or a (substituted) aralkyl group suchas a tert-butyl group, a benzyl group, a p-nitrobenzyl group, ap-methoxybenzyl group or a triphenylmethyl group; (substituted) etherssuch as a methoxymethyl group, a tert-butoxymethyl group, atetrahydropyranyl group and a 2,2,2-trichloroethoxymethyl group; and(alkyl and/or aralkyl)-substituted silyl groups such as a trimethylsilylgroup, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group,a tribenzylsilyl group and a tert-butyldiphenylsilyl group.

The following compound (B) can be cited as a preferable compound amongthe compound (3):

[In this formula, each of R¹⁹ and R²⁰ independently represents ahydrogen atom, a lower alkyl group or an amino-substituted cyclopropylgroup (this amino group may have a substituent or a protective group),or R¹⁹ and R²⁰ may be combined into a group represented by the followingformula:

—(CH₂)₂—

and form a spiro cyclic structure together with the pyrrolidine ring,and R²¹ represents a halogen atom or an amino group which may have asubstituent or a protective group.]

R¹⁹, R²⁰ and R²¹ are substituents on the pyrrolidine ring. Among them,each of R¹⁹ and R²⁰ is independently a hydrogen atom, a lower alkylgroup or an amino-substituted cyclopropyl group (this amino group mayhave a substituent or a protective group), or R¹⁹ and R²⁰ may becombined into a group represented by the following formula:

—(CH₂)₂—

and form a spiro cyclic structure together with the pyrrolidine ring.R²¹ is a halogen atom or an amino group which may have a substituent ora protective group.

When each of R¹⁹ and R²⁰ is a lower alkyl group, it may be either astraight chain or a brunched chain group having from 1 to 6 carbon atomsand may further contain a cyclic moiety. Illustrative examples of thealkyl group include a methyl group, an ethyl group and an isopropylgroup.

Each of R¹⁹ and R²⁰ may also be an amino-substituted cyclopropyl group,namely a cyclopropyl group, in which an amino group which may have asubstituent or a protective group is substituted on the cyclopropanering.

The protective group of the amino group on the cyclopropane ring is notparticularly limited, with the proviso that it is generally used in thisfield, and those exemplified in the foregoing may be used.

A lower alkyl group can be cited as the substituent other thanprotective group, and its examples include similar lower alkyl groupsdescribed in the foregoing.

Regarding substitution position of the amino group on the cyclopropylgroup, on the carbon atom where cyclopropyl group binds to the7-position of the quinolone mother nucleus can be cited, though it maybe other position than this.

When R²¹ is a halogen atom, it is a fluorine atom or a chlorine atom.Also, when it is an amino group which may have a substituent or aprotective group, these substituent and protective group can be regardedas the same case of the amino group when R¹⁹ or R²⁰ is anamino-substituted cyclopropyl group.

Similar to the case of the R¹⁹, R²⁰ and R²¹, R²², R²³ and R²⁴ aresubstituents on the pyrrolidine ring. Different point in the R²², R²³and R²⁴ is that they are amino groups resulting from the elimination ofprotective groups from the R¹⁹, R²⁰ and R²¹ or they are substituentscontaining the protective group-eliminated amino group, and the case ofother substituents can be considered in the same manner.

The following can be cited as more preferred examples of the substituentR:

Each step regarding the production method of the invention is describedin the following in detail using a 5-amino-8-methylquinolone compound asan example.

A Step for Producing the Compound (A) [from a Compound (E)]

In this step, the amino group of the 5-position (or a correspondingposition) of the quinolone skeleton is converted into an acylamino groupby an acylation reaction. In this connection, the boron chelationreaction is a reaction in which a boron-containing substituent isintroduced into a carboxyl group moiety, which may be an ester, at the3-position (or a corresponding position), and the present inventors havefound that these reactions can be carried out simultaneously. As anexample of the starting material of these reactions, a compound offormula (E):

(wherein X¹ is a hydrogen atom or a halogen atom, X² and X³ are eachindependently a halogen atom, and R²⁵ is a hydrogen atom or an alkylgroup having from 1 to 6 carbon atoms) can be used.

An acid anhydride or an acid halide can be used as the acylation agentto be used in the acylation reaction of this step. Examples of the acidanhydride include acetic anhydride, trifluoroacetic anhydride,phenylacetic anhydride, propionic anhydride and benzoic anhydride.Examples of the acid halide include acetyl chloride, acetyl bromide,propionyl chloride and benzoic acid chloride.

The acylation agent is used in an amount of from one equivalent to largeexcess based on the compound (E). When an acid halide is used, it ispreferable to simultaneously use tertiary amines such as triethylamineand pyridine or a nitrogen-containing heterocyclic compound (any one ofaromatic, saturated and partially saturated compounds).

When the acylation reaction and boron chelating reaction aresimultaneously carried out, it is preferable as an acylation agent touse an acid chloride which does not require a base, and the reactionscan be carried out under the above reaction conditions.

As the boron chelating agent to be used for the boron chelatingreaction, a boron compound capable of forming a boron chelate withcarboxyl group or carbonyl group is used. Illustratively, borontrihalide compounds are used, and ether complexes of these trihaloboroncompounds can be used suitably. For example, a boron trifluoride diethylether complex and a boron trifluoride tetrahydrofuran complex can becited. Tetrafluoroboric acid as an analogous compound of trifluoroboroncan also be used. By allowing them to undergo the reaction, adihaloboron group, particularly difluoroboron group can be introduced.Tetrafluoroboric acid is particularly preferable as the agent forsimultaneously carrying out both of acylation and boron chelation by thereaction in the presence of an acid anhydride.

As the boron-containing group, it may be not only a halogen-substitutedboron group but also an acyloxy-substituted boron group. Introduction ofthe acyloxyboron group can be carried out by preparing an acyloxyboronchelating reagent in advance from boric acid and an acid anhydride andallowing it to undergo the reaction.

Amount of the boron chelating agent to be used is within the range offrom 1 equivalent to 10 equivalents, preferably within the range of from1 equivalent to 5 equivalents, based on the compound (E).

This reaction can be carried out in a solvent, and any solvent inert tothe reaction can be used. Examples of the solvent include an aromatichydrocarbon solvent such as toluene or xylene; an ester solvent such asethyl acetate; an ether solvent such as tetrahydrofuran or diethylether; a ketone solvent such as acetone or methyl isobutyl ketone; anitrile solvent such as acetonitrile; an amide solvent such asdimethylformamide, dimethylacetamide or N-methylpyrrolidone; a sulfoxidesolvent such as dimethyl sulfoxide; and a chlorine solvent such asdichloromethane or chloroform. In addition, an acylation reagent itselfmay be used also as the solvent. Particularly, when an acid anhydride isused as the acylation reagent, it is preferable to use it also as thesolvent. The solvent may be used in an amount of from 5 to 20 volumesbased on the compound (E) (e.g., at a ratio of from 5 ml to 20 ml per 1g of the compound (E)).

The reaction temperature is within the range of from −30° C. to refluxtemperature of the solvent or acylation agent. Also, the reaction timeis generally within the range of from 1 to 10 hours.

In this step, there are two ways of selection, namely only the acylationis carried out or the acylation and boron chelation are simultaneouslycarried out. When the subsequent step in which a basic substituent isintroduced into the 7-position is taken into consideration, a compoundobtained by simultaneously carrying out the acylation and boronchelation has superior reactivity with the basic substituent compound,so that it is preferable to carry out this reaction. In that case,difluoroboron chelation is preferable as the boron chelation due toeasiness of the reaction. That is, it is preferable to carry out thereaction of an acid hydride with dihaloboron chelation agent.Illustratively, it is preferable that the amino group is acetylated byallowing acetic anhydride to react with tetrafluoroboric acid, whiledifluoroboron group is introduced into the carboxyl group moiety.

A Step in Which a Basic Substituent Compound (R—H) is Allowed to Undergothe Reaction

In order to obtain the compound (2), a basic substituent compound

R—H

(wherein R is as defined in the foregoing)

is allowed to react with the compound (1) under a high pressure in thepresence or absence of a solvent. In this case, a base as an acidreceptor may be added as occasion demands.

Amount of the basic substituent compound to be used in the productionmethod of the invention is within the range of from 1 to 10 moles,preferably within the range of from 1 to 3 moles, more preferably withinthe range of from 1 to 1.5 moles, based on 1 mole of the quinolonecompound represented by the general formula (1).

The organic solvent to be used in the production method of the inventionis not particularly limited, with the proviso that it is inert to thereaction, and its examples include an aromatic hydrocarbon solvent suchas toluene or xylene, an ester solvent such as ethyl acetate, an ethersolvent such as tetrahydrofuran or diethyl ether, a ketone solvent suchas acetone or methyl isobutyl ketone, a nitrile solvent such asacetonitrile, an amide solvent such as dimethylformamide,dimethylacetamide or 1,3-dimethyl-2-imidazolidinone, a sulfoxide solventsuch as dimethyl sulfoxide, a sulfone solvent such as sulfolane, and achlorine solvent such as dichloromethane or chloroform, of whichacetonitrile, dimethylformamide, 1,3-dimethyl-2-imidazolidinone,dimethyl sulfoxide and sulfolane are preferable. In this connection, useof the solvent is not necessary in some cases, so that the presence ofthe reaction solvent is not essential.

Examples of the base as an acid receptor to be used as occasion demandsin the production method of the invention generally include organicamines including a trialkylamine, an aryldialkylamine and an(N-substituted) heterocyclic compound, such as triethylamine,N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene,1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]-5-nonene andpyridine, and inorganic bases including alkali metal or alkaline earthmetal salts of carbonic acid or hydrogen carbonic acid compound, such assodium carbonate, potassium carbonate, sodium bicarbonate and potassiumbicarbonate. Amount of the base to be used may be from the sameequivalent to excess amount, but it is general to use up toapproximately 3 equivalents.

The reaction of the production method of the invention is carried out ata temperature within a range of up to boiling point of the solvent to beused, with the lower limit of 0° C. and the upper limit of 200° C., butwhen a boron-chelated quinolone compound is used, the lower limit is 0°C., preferably 40° C., and the upper limit is 80° C., preferably 50° C.

Pressure during the reaction of the production method of the inventionis 1×10⁷ Pa, preferably 1.5×10⁷ Pa, as the lower limit, and 5×10⁸ Pa,preferably 3.5×10⁸ Pa, as the upper limit.

The reaction under a high pressure is carried out in a reaction vesselwhich can sufficiently withstand such a high pressure. The followingshows a series of the high pressure reaction steps.

(1) A reaction solution prepared by dissolving the material andnecessary agents is transferred into a high pressure reaction vessel,and inside of the high pressure reaction vessel is heated to apredetermined temperature.

(2) After confirming that the temperature became constant, the reactionsolution is directly pressurized to a predetermined pressure using apiston connected to a hydraulic pump and hydraulic cylinder.

(3) The reaction is carried out by allowing the solution to stand for apredetermined period of time while keeping the temperature, and then thereaction solution is returned to ordinary pressure and taken out.

Though the reaction time in the production method of the invention isnot particularly limited, it is approximately from 3 to 24 hours, but aportion of the material remains in some cases even when the reaction iscarried out in this manner. In that case, yield of the product ofinterest can be improved by once suspending the reaction to recover thematerial and then subjecting it again to the reaction. According to themethod of the invention, decomposition of the material compound can beprevented so that the material compound can be recovered to a recyclabledegree, which is useful.

The substitution reaction of the basic substituent compound can becarried out by the following reaction. For example, the compound (C) canbe obtained by allowing the compound (A) to react with the compound (B)in the presence or absence of a base, but, in this case, pressurizationmay not be necessary depending on the structure of X³ and compound (B):

The base to be used may be the same as the above case, and its examplesinclude organic compounds such as a nitrogen-containing heterocycliccompound (aromatic, saturated or partially saturated), a tertiary aminecompound and a secondary amine compound (an aromatic hydrocarbon system,an aliphatic system, an aralkyl system and a nitrogen-containingheterocyclic system can be exemplified based on the kind ofsubstituents, and the substituents maybe either a single system or ascramble system of them). In addition to the compounds cited in theforegoing, its illustrative examples include pyridine,4-dimethylaminopyridine, triethylamine, tributylamine,N-methylpiperidine, DBU, diisopropylamine, dibenzylamine and2,2,6,6-tetramethylpiperidine. It may also be an inorganic base, and itsexamples include carbonate, hydroxide or bicarbonate of an alkali metalcompound or alkaline earth metal compound, such as potassium carbonateand potassium hydroxide. Also useful as the base are sodium hydride andpotassium tert-butoxide as an alkoxide.

The base may be used in an amount of from 1 to 10 equivalents based onthe compound (A).

This reaction is generally carried out in a solvent, and any solventinert to the reaction can be used. Examples of the solvent include anaromatic hydrocarbon solvent such as toluene or xylene; an ester solventsuch as ethyl acetate; an ether solvent such as tetrahydrofuran ordiethyl ether; a ketone solvent such as acetone or methyl isobutylketone; a nitrile solvent such as acetonitrile; an amide solvent such asdimethylformamide, dimethylacetamide or 1,3-dimethyl-2-imidazolidinone;a sulfoxide solvent such as dimethyl sulfoxide; a sulfone solvent suchas sulfolane; and a chlorine solvent such as dichloromethane orchloroform. Among them, acetonitrile, dimethylformamide,dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, dimethyl sulfoxideand sulfolane are preferable. These solvent may be used in an amount ofapproximately from 2 to 50 volumes based on the compound (A).

The reaction temperature is within the range of from 0° C. to refluxtemperature of the solvent to be used, preferably within the range of30° C. to 90° C., but when the compound (A) is a boron-chelatedcompound, a range of from 30° C. to 50° C. is particularly preferable.Also, the reaction time is generally within the range of from 15 hoursto 20 days.

A Step in Which a Compound (D) is Produced from the Compound (C)

A compound (D) can be obtained by hydrolysis reaction of the compound(C). In the hydrolysis reaction of this step, acylated amino group andboron-chelated carboxyl group are respectively converted into aminogroup and carboxyl group. When a protective group is present, a step forits elimination is also included.

This reaction can be carried out under a known hydrolysis reactioncondition such as an acidic condition or an alkaline condition. Examplesof the acid to be used in the hydrolysis reaction under an acidiccondition include inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid and phosphoric acid and organic acids such astrifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid andtrifluoromethanesulfonic acid. As the hydrolysis with acid, hydrolysisusing an inorganic acid is preferable. Also, examples of the alkali tobe used in the hydrolysis reaction under an alkaline condition includesodium hydroxide and potassium hydroxide.

This reaction can be carried out in an aqueous solution of the aboveacid or alkali but can also be carried out in an organic solvent such asmethanol, ethanol or isopropanol or in a water-containing organicsolvent, and the solvent is used in an amount of from 5 to 20 volumesbased on the compound (C).

The reaction temperature is within the range of from 0° C. to refluxtemperature of the solvent to be used. Also, the reaction time isgenerally within the range of from 1 to 10 hours.

Since an amino group is present in the compound (B) used in the reactionto obtain the compound (C), when this amino group has a protectivegroup, it is necessary to remove this protective group. Removingreaction of the protective group may be carried out at the same timewith the above hydrolysis reaction when the same conditions can be used.When deprotection is carried out independently from the hydrolysisreaction, the protective group can be removed by a known methoddepending on the kind of used protective group.

The compound (C-1) is a compound in which an acyl group of the aminogroup is removed, and the compound (C-2) is a compound in which aprotective group on a substituent, particularly the protective group ofamino group, is removed. Since the above deprotection reaction can beeffected by stepwise removal of protective groups, these compounds canbe obtained.

In addition, when R¹⁸ is an ester, it may be hydrolyzed under an acidicor basic condition. When R¹⁸ is a boron chelate, it can be convertedinto carboxylic acid through cleavage of the boron chelate by heattreatment in a protic solvent if necessary in the presence of a base.

BEST MODE FOR CARRYING OUT THE INVENTION

The invention is described further in detail with reference to examples,though the scope of the invention is not limited thereto. Analyticalconditions of the high performance liquid chromatography (to be referredto as HPLC hereinafter) in the examples are as follows.

HPLC analysis conditions

CONDITIONS IN COMPARATIVE EXAMPLES 13 and 14 and INVENTIVE Examples 13and 14

Column: ODS-80TM;

Elution solvent: 0.05 mmol/L KH₂PO₄ aqueous solution (pH3):acetonitrile=40:60 (V/V);

Flow rate: 1.0 ml/min;

Detection wavelength: 275 nm;

CONDITIONS IN COMPARATIVE EXAMPLES 15 to 17 and INVENTIVE Examples 15 to17

Column: Symmetry C18 5 μm 4.6×150 mm;

Elution solvent: 0.03 mmol/L KH₂PO₄ aqueous solution (pH2.4):acetonitrile=60:40 (V/V);

Flow rate: 1.0 ml/min;

Detection wavelength: 230 nm

INVENTIVE EXAMPLE 1

Ethyl5-diacetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate

A mixture consisting of ethyl5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate(1.00 g), acetic anhydride (20 ml) and triethylamine (0.94 g) wasstirred at an outer temperature of 100° C. for 4 hours. This wasconcentrated under a reduced pressure, and the resulting crystals werecollected by filtration and washed by acetonitrile to obtain 0.90 g(71.7%) of light yellow crystals.

¹H-NMR (DMSO-d₆) δ: 8.54 (d, J=2.6 Hz, 1 H), 5.23-4.93 (m, 1 H), 4.24(q, J=7.0 Hz, 3 H), 4.23-4.15 (m, 1 H), 2.63 (d, J=3.0 Hz, 3 H), 2.15(s, 3 H), 2.08 (s, 3 H), 1.68-1.30 (m, 2 H), 0.91-0.49 (t, J=7.0 Hz, 2H)

INVENTIVE EXAMPLE 2

[5-Acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid-O³,O⁴]difluoroboron

A mixture consisting of5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (1.01 g), acetic anhydride (10 ml) and 42% tetrafluoroboric acid(0.72 g) was stirred at room temperature for 1 hour. This wasconcentrated under a reduced pressure, and ethyl acetate was added tothe residue to collect the resulting crystals by filtration. Byrecrystallizing from an acetone-hexane, 0.37 g (28.9%) of light yellowcrystals were obtained.

¹H-NMR (DMSO-d₆) δ: 10.22 (s, 1 H), 9.39 (d, J=2.6 Hz, 1 H), 5.34-5.05(m, 1 H), 4.72-4.65 (m, 1 H), 2.81 (d, J=3.3 Hz, 3 H), 2.12 (s, 3 H),1.88-1.74 (m, 2 H)

INVENTIVE EXAMPLE 3

[5-Diacetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid-O³,O⁴]difluoroboron

A mixture consisting of5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (1.00 g), acetic anhydride (10 ml) and 42% tetrafluoroboric acid(0.73 g) was stirred at an outer temperature of 100° C. for 2 hours.This was concentrated under a reduced pressure, and water was added tothe residue to collect the resulting crystals by filtration. Byrecrystallizing from an acetone-water, 0.50 g (35.0%) of light yellowcrystals were obtained.

¹H-NMR (DMSO-d₆) δ: 9.47 (d, J=2.6 Hz, 1 H), 5.38-5.08 (m, 1 H),4.82-4.74 (m, 1 H), 2.92 (d, J=3.6 Hz, 3 H), 2.31 (s, 3 H), 1.25 (s, 3H), 1.92-1.80 (m, 2 H)

INVENTIVE EXAMPLE 4

5-Acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid

A mixture consisting of5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (4.95 g), acetic anhydride (50 ml) and tetrafluoroboric acid (4.30g) was stirred at room temperature for 1 hour. This was concentratedunder a reduced pressure, and ethyl acetate was added to the residue tocollect the resulting crystals by filtration. Next, a mixture consistingof the crystals, ethanol (106 ml) and triethylamine (4.2 ml) was stirredat an outer temperature of 80° C. for 30 minutes. This was concentratedunder a reduced pressure and acetone was added to the residue to collectthe resulting crystals by filtration, thereby obtaining 4.62 g (82.1%)of light yellow crystals.

¹H-NMR (DMSO-d₆) δ: 10.36 (s, 1 H), 8.81 (d, J=3.0 Hz, 1 H), 5.25-4.99(m, 1 H), 4.39-4.32 (m, 1 H), 2.70 (d, J=3.3 Hz, 3 H), 2.15 (s, 3 H),1.73-1.45 (m, 2 H)

INVENTIVE EXAMPLE 5

Ethyl5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylate

A mixture consisting of ethyl5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate(1.01 g), acetic anhydride (20 ml) and triethylamine (0.95 g) wasstirred at an outer temperature of 70° C. for 10 hours. This was cooledwith ice and the precipitated crystals were collected by filtration, andthe filtrate was further concentrated under a reduced pressure tocollect the precipitated crystals by filtration, thereby obtaining 0.90g (78.8%) of white crystals.

¹H-NMR (DMSO-d₆) δ: 11.20 (s, 1 H), 8.58 (s, 1 H), 4.27-4.19 (m, 1 H),4.23 (q, J=6.9 Hz, 2 H), 2.70 (d, J=3.3 Hz, 3 H), 2.14 (s, 3 H), 1.28(t, J=6.9 Hz, 3 H), 1.18-1.11 (m, 2 H), 0.92-0.86 (m, 2 H)

INVENTIVE EXAMPLE 6

[5-Acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicAcid-O³,O⁴]difluoroboron

A mixture consisting of5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (5.89 g), acetic anhydride (58.9 ml) and 42% tetrafluoroboric acid(5.02 g) was stirred at an outer temperature of 110° C. for 4 hours.This was cooled with ice, and the thus precipitated crystals werecollected by filtration and washed with water and acetonitrile to obtain6.19 g (80.6%) of light yellow crystals.

¹H-NMR (DMSO-d₆) δ: 10.14 (s, 1 H), 9.30 (s, 1 H), 4.79-4.65 (m, 1 H),2.89 (d, J=3.6 Hz, 3 H), 2.11 (s, 3 H), 1.33-1.25 (m, 2 H), 1.25-1.16(m, 2 H)

INVENTIVE EXAMPLE 7

5-Trifluoroacetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid

A mixture consisting of5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (1.47 g) and trifluoroacetic anhydride (7.1 ml) was stirred underice-cooling for 1 hour. This was mixed with water and the thusprecipitated crystals were collected by filtration and washed with waterand ethanol to obtain 1.88 g (96.6%) of light yellow crystals.

¹H-NMR (DMSO-d₆) δ: 14.36 (br s, 1 H), 11.79 (br s, 1 H), 8.86 (s, 1 H),4.44-4.37 (m, 1 H), 2.82 (d, J=3.6 Hz, 3 H), 1.26-1.19 (m, 2 H),1.05-1.00 (m, 2 H)

INVENTIVE EXAMPLE 8

5-Acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid

A mixture consisting of5-acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (50.2 mg),(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine(53.1 mg) and dimethyl sulfoxide (0.25 ml) was stirred at an outertemperature of 80° C. for 38 hours. When quantitative analysis wascarried out by a high performance liquid chromatography after completionof the reaction, formed amount of the compound of interest5-acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid corresponded to 63.0 mg. The formation ratio was 76.8%.

¹H-NMR (DMSO-d₆) δ: 10.01 (s, 1 H), 8.69 (d, J=3.0 Hz, 1 H), 7.24 (s, 1H), 5.39-5.21 (m, 1 H), 5.19-4.96 (m, 1 H), 4.25-4.17 (m, 1 H),4.09-4.04 (m, 1 H), 3.90-3.78 (m, 1 H), 3.44-3.32 (m, 2 H), 2.78-2.64(m, 1 H), 2.38 (s, 3 H), 2.10 (s, 3 H), 1.64-1.14 (m, 2 H), 1.38 (s, 9H), 0.91-6.61 (m, 4 H)

INVENTIVE EXAMPLE 9

5-Acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid

A mixture consisting of5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (51.2 mg), (7S)-7-tert-butoxycarbonylamino-5-azaspiro(2.4)heptane(48.2 mg) and dimethyl sulfoxide (0.25 ml) was stirred at an outertemperature of 95° C. for 20 hours. When quantitative analysis wascarried out by a high performance liquid chromatography after completionof the reaction, formed amount of the compound of interest5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid corresponded to 68.9 mg. The formation ratio was 85.6%.

¹H-NMR (DMSO-d₆) δ: 10.08 (s, 1 H), 8.74 (s, 1 H), 7.32-7.17 (m, 1 H),4.38-4.20 (m, 1 H), 4.00-3.82 (m, 2 H), 3.77 (d, J=9.6 Hz, 1 H),3.55-3.42 (m, 1 H), 3.31 (d, J=9.6 Hz, 1 H), 2.51 (s, 3 H), 2.10 (s, 3H), 1.39 (s, 9 H), 1.34-1.08 (m, 3 H), 0.91-0.49 (m, 5 H)

INVENTIVE EXAMPLE 10

5-Acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid

A mixture consisting of[5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid-O³,O⁴]difluoroboron (10.8 g),(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (8.29 g),1-methylpiperidine (6.64 g) and dimethyl sulfoxide (50 ml) was stirredat an outer temperature of 40° C. for 2 days and then stirred at anouter temperature of 80° C. for 3 days. The reaction solution was mixedwith water (200 ml) and extracted with ethyl acetate. Next, the organiclayer was washed with 10% citric acid aqueous solution and water anddried over anhydrous sodium sulfate, insoluble material was removed byfiltration and then the filtrate was concentrated under a reducedpressure to obtain 17.3 g (purity 76.7%, yield 89.4%) of yellowcrystals.

¹H-NMR (DMSO-d₆) δ: 10.08 (s, 1 H), 8.74 (s, 1 H), 7.32-7.17 (m, 1 H),4.38-4.20 (m, 1 H), 4.00-3.82 (m, 2 H), 3.77 (d, J=9.6 Hz, 1 H),3.55-3.42 (m, 1 H), 3.31 (d, J=9.6 Hz, 1 H), 2.51 (s, 3 H), 2.10 (s, 3H), 1.39 (s, 9 H), 1.34-1.08 (m, 3 H), 0.91-0.49 (m, 5 H)

INVENTIVE EXAMPLE 11

5-Amino-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid

A 20% sodium hydroxide aqueous solution (169 ml) was added to 84.5%purity5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (14.1 g) under stirring at room temperature, and the mixture wasstirred at 80° C. for 8 hours. This was extracted with ethyl acetate,the organic layer was washed with saturated ammonium chloride aqueoussolution and saturated brine and dried over sodium sulfate, theinsoluble matter was removed by filtration, and then the filtrate wasconcentrated under a reduced pressure to obtain 10.4 g of yellowcrystals. A mixture consisting of the crystals (8.87 g), concentratedhydrochloric acid (11 ml) and water (10 ml) was stirred at roomtemperature for 2 hours. While ice-cooling and stirring, the reactionsolution was mixed with 33 g of 30% potassium hydroxide aqueous solutionand adjusted to pH 8 with 10% hydrochloric acid. The thus precipitatedcrystals were collected by filtration, and the filtrate was concentratedunder a reduced pressure, mixed with methanol to remove the insolublematter by filtration and then concentrated under a reduced pressure toobtain crystals. They were combined with the crystals firstly collectedby filtration, thereby obtaining 6.89 g (purity 76.2%, yield 71%) ofyellow crystals.

¹H-NMR (DMSO-d₆) δ: 8.61 (s, 1 H), 7.13 (s, 2 H), 6.60-4.60 (br s, 2 H),4.21-4.06 (m, 1 H), 3.88-3.73 (m, 1 H), 3.61 (d, J=8.6 Hz, 1 H), 3.44(d, J=8.6 Hz, 1 H), 3.36-3.23 (m, 1 H), 3.20-3.11 (m, 1 H), 2.33 (s, 3H), 1.25-0.38 (m, 8 H)

INVENTIVE EXAMPLE 12

5-Amino-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid

A 20% sodium hydroxide aqueous solution (4.8 ml) was added to 76.7%purity5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (400.1 mg) under stirring at room temperature, and the mixture wasstirred at 80° C. for 5 hours. While stirring at room temperature, thereaction solution was mixed with concentrated hydrochloric acid andstirred for 1 hour. When quantitative analysis was carried out by a highperformance liquid chromatography after neutralization of the reactionsolution by adding 20% sodium hydroxide aqueous solution, formed amountof the compound of interest5-amino-7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid corresponded to 207.2 mg. The formation ratio was 92%.

¹H-NMR (DMSO-d₆) δ: 8.61 (s, 1 H), 7.13 (s, 2 H), 6.60-4.60 (br s, 2 H),4.21-4.06 (m, 1 H), 3.88-3.73 (m, 1 H), 3.61 (d, J=8.6 Hz, 1 H), 3.44(d, J=8.6 Hz, 1 H), 3.36-3.23 (m, 1 H), 3.20-3.11 (m, 1 H), 2.33 (s, 3H), 1.25-0.38 (m, 8 H)

EXAMPLE 13

5-Acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid

Comparative Example 13

A mixture consisting of5-acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (54.4 mg, 0.154 mmol),(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine(54.5 mg, 0.223 mmol), 1-methylpiperidine (51.3 mg, 0.517 mmol) anddimethyl sulfoxide (0.25 ml) was stirred at an outer temperature of 80°C. for 7 hours. When analysis was carried out by a high performanceliquid chromatography after completion of the reaction, formed ratio ofthe compound of interest5-acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 49%. Also, residual ratio of the material was 34%.

¹H-NMR (DMSO-d₆) δ: 10.01 (s, 1 H), 8.69 (d, J=3.0 Hz, 1 H), 7.24 (s, 1H), 5.39-5.21 (m, 1 H), 5.19-4.96 (m, 1 H), 4.25-4.17 (m, 1 H),4.09-4.04 (m, 1 H), 3.90-3.78 (m, 1 H), 3.44-3.32 (m, 2 H), 2.78-2.64(m, 1 H), 2.38 (s, 3 H), 2.10 (s, 3 H), 1.64-1.14 (m, 2 H), 1.38 (s, 9H), 0.91-0.61 (m, 4 H)

INVENTIVE EXAMPLE 13

A) A mixture consisting of5-acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (2.60 g, 7.34 mmol),(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine(2.69 g, 11.0 mmol), 1-methylpiperidine (1.34 ml, 11.1 mmol) anddimethyl sulfoxide (13 ml) was heated at an outer temperature of 80° C.for 7 hours under a condition of 2.94×10⁸ Pa (converted from 3,000kgf/cm²). When analysis was carried out by a high performance liquidchromatography after completion of the reaction, formed ratio of thecompound of interest5-acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 72%. Also residual ratio of the material was 11%.

¹H-NMR (DMSO-d₆) δ: 10.01 (s, 1 H), 8.69 (d, J=3.0 Hz, 1 H), 7.24 (s, 1H), 5.39-5.21 (m, 1 H), 5.19-4.96 (m, 1 H), 4.25-4.17 (m, 1 H),4.09-4.04 (m, 1 H), 3.90-3.78 (m, 1 H), 3.44-3.32 (m, 2 H), 2.78-2.64(m, 1 H), 2.38 (s, 3 H), 2.10 (s, 3 H), 1.64-1.14 (m, 2 H), 1.38 (s, 9H), 0.91-0.61 (m, 4 H)

B) A dimethyl sulfoxide (15 ml) solution containing5-acetylamino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (3.0 g, 8.47 mmol),(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine(3.19 g, 12.7 mmol) and 1-methylpiperidine (1.54 ml, 12.7 mmol) washeated at an outer temperature of 80° C. for 22 hours under a conditionof 2.94×10⁸ Pa. The reaction solution was washed with ethyl acetate toadjust the total volume to 128 ml and then washed twice with 5% citricacid aqueous solution (30 ml) to separate the organic phase and aqueousphase. The aqueous phase was extracted three times with ethyl acetate,combined with the above organic phase and then extracted three timeswith 5% potassium hydroxide aqueous solution (30 ml). To the aqueousphase were added chloroform (90 ml) and then 3 N hydrochloric acid untilpH became 4, thereby separating the organic phase and aqueous phase. Theaqueous phase was extracted twice with chloroform, combined with theabove organic phase and then dried over anhydrous sodium sulfate. Byevaporating the solvent under a reduced pressure,5-acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (4.92 g, purity 90.0%, yield 89.2%) was obtained as yellowamorphous.

EXAMPLE 14

5-Amino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid

Comparative Example 14

A mixture consisting of5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (45 mg, 0.144 mmol),(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidine(52.8 mg, 0.216 mmol), 1-methylpiperidine (18.5 mg, 0.186 mmol) anddimethyl sulfoxide (1.8 ml) was stirred at an outer temperature of 80°C. for 7 hours. When analysis was carried out by a high performanceliquid chromatography after completion of the reaction, formed ratio ofthe compound of interest5-amino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 4%. Also, residual ratio of the starting material was 90%.

¹H-NMR (CDCl₃) δ: 14.8 (s, 1 H), 8.60 (d, J=3.4 Hz, 1 H), 6.52 (brs, 1H), 5.28 (dm, J=54.7 Hz, 1 H), 4.85 (dm, J=63.0 Hz, 1 H), 4.11-4.13 (m,1 H), 3.80-3.88 (m, 2 H), 3.35-3.54 (m, 2 H), 2.30-2.35 (m, 1 H), 2.29(s, 3 H), 1.45 (s, 9 H), 1.24-1.28 (m, 1 H), 1.00-1.02 (m, 2 H),0.88-0.90 (m, 1 H), 0.77-0.79 (m, 1 H)

INVENTIVE EXAMPLE 14

A mixture consisting of5-amino-6,7-difluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (0.33 g, 1.06 mmol),(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoro pyrrolidine(0.39 g, 1.60 mmol), 1-methylpiperidine (0.16 ml, 1.33 mmol) anddimethyl sulfoxide (13 ml) was heated at an outer temperature of 80° C.for 7 hours under a condition of 2.94×10⁸ Pa. When analysis was carriedout by a high performance liquid chromatography after completion of thereaction, formed ratio of the compound of interest5-acetylamino-7-[(3S,4R)-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-fluoropyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 17%. Also, residual ratio of the starting material was 79%.

¹H-NMR (CDCl₃) δ: 14.8 (s, 1 H), 8.60 (d, J=3.4 Hz, 1 H), 6.52 (brs, 1H), 5.28 (dm, J=54.7 Hz, 1 H), 4.85 (dm, J=63.0 Hz, 1 H), 4.11-4.13 (m,1 H), 3.80-3.88 (m, 2 H), 3.35-3.54 (m, 2 H), 2.30-2.35 (m, 1 H), 2.29(s, 3 H), 1.45 (s, 9 H), 1.24-1.28 (m, 1 H), 1.00-1.02 (m, 2 H),0.88-0.90 (m, 1 H), 0.77-0.79 (m, 1 H)

EXAMPLE 15

5-Acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid

Comparative Example 15

A mixture consisting of5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (48.7 mg, 0.145 mmol),(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (45.7 mg, 0.215mmol), triethylamine (30.8 mg, 0.304 mmol) and dimethyl sulfoxide (0.25ml) was stirred at an outer temperature of 80° C. for 7 hours. Whenanalysis was carried out by a high performance liquid chromatographyafter completion of the reaction, formed ratio of the compound ofinterest5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 58%. Also, residual ratio of the starting material was 29%.

¹H-NMR (DMSO-d₆) δ: 10.08 (s, 1 H), 8.74 (s, 1 H), 7.32-7.17 (m, 1 H),4.38-4.20 (m, 1 H), 4.00-3.82 (m, 2 H), 3.77 (d, J=9.6 Hz, 1 H),3.55-3.42 (m, 1 H), 3.31 (d, J=9.6 Hz, 1 H), 2.51 (s, 3 H), 2.10 (s, 3H), 1.39 (s, 9 H), 1.34-1.08 (m, 3 H), 0.91-0.49 (m, 5 H)

INVENTIVE EXAMPLE 15

A mixture consisting of5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (2.60 g, 7.75 mmol),(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (2.46 g, 11.6mmol), triethylamine (1.62 ml, 11.7 mmol) and dimethyl sulfoxide (13 ml)was heated at an outer temperature of 80° C. for 7 hours under acondition of 2.94×10⁸ Pa. When analysis was carried out by a highperformance liquid chromatography after completion of the reaction,formed ratio of the compound of interest5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 77%. Also, residual ratio of the starting material was 10%.

¹H-NMR (DMSO-d₆) δ: 10.08 (s, 1 H), 8.74 (s, 1 H), 7.32-7.17 (m, 1 H),4.38-4.20 (m, 1 H), 4.00-3.82 (m, 2 H), 3.77 (d, J=9.6 Hz, 1 H),3.55-3.42 (m, 1 H), 3.31 (d, J=9.6 Hz, 1 H), 2.51 (s, 3 H), 2.10 (s, 3H), 1.39 (s, 9 H), 1.34-1.08 (m, 3 H), 0.91-0.49 (m, 5 H)

EXAMPLE 16

5-Acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid

Comparative Example 16

A mixture consisting of[5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid-O³,O⁴]difluoroboron (50 mg, 0.130 mmol),(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (41.5 mg, 0.195mmol), triethylamine (19.7 mg, 0.195 mmol) and dimethylformamide (4.5ml) was stirred at an outer temperature of 40° C. for 7 hours. Whenanalysis was carried out by a high performance liquid chromatographyafter completion of the reaction, formed ratio of the compound ofinterest5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 11%. Also, residual ration of the starting material was 87%.

¹H-NMR (DMSO-d₆) δ: 10.08 (s, 1 H), 8.74 (s, 1 H), 7.32-7.17 (m, 1 H),4.38-4.20 (m, 1 H), 4.00-3.82 (m, 2 H), 3.77 (d, J=9.6 Hz, 1 H),3.55-3.42 (m, 1 H), 3.31 (d, J=9.6 Hz, 1 H), 2.51 (s, 3 H), 2.10 (s, 3H), 1.39 (s, 9 H), 1.34-1.08 (m, 3 H), 0.91-0.49 (m, 5 H)

INVENTIVE EXAMPLE 16

A mixture consisting of[5-acetylamino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid-O³,O⁴]difluoroboron (0.20 g, 0.521 mmol),(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (0.17 g, 0.810mmol), triethylamine (0.11 ml, 0.794 mmol) and dimethylformamide (18 ml)was heated at an outer temperature of 40° C. for 7 hours under acondition of 2.94×10⁸ Pa. When analysis was carried out by a highperformance liquid chromatography after completion of the reaction,formed ratio of the compound of interest5-acetylamino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 32%. Also, residual ratio of the starting material was 51%.

¹H-NMR (DMSO-d₆) δ: 10.08 (s, 1 H), 8.74 (s, 1 H), 7.32-7.17 (m, 1 H),4.38-4.20 (m, 1 H), 4.00-3.82 (m, 2 H), 3.77 (d, J=9.6 Hz, 1 H),3.55-3.42 (m, 1 H), 3.31 (d, J=9.6 Hz, 1 H), 2.51 (s, 3 H), 2.10 (s, 3H), 1.39 (s, 9 H), 1.34-1.08 (m, 3 H), 0.91-0.49 (m, 5 H)

EXAMPLE 17

5-Amino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoguinoline-3-carboxylicacid

Comparative Example 17

A mixture consisting of5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (50 mg, 0.170 mmol),(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (108 mg, 0.509mmol) and dimethyl sulfoxide (4 ml) was stirred at an outer temperatureof 80° C. for 7 hours. When analysis was carried out by a highperformance liquid chromatography after completion of the reaction,formed ratio of the compound of interest5-amino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 10%. Also, residual ratio of the starting material was 90%.

¹H-NMR (DMSO-d₆) δ: 8.62 (s, 1 H), 7.20 (s, 1 H), 7.18 (s, 2 H),4.17-4.14 (m, 1 H), 3.90-3.88 (m, 2 H), 3.71-3.68 (m, 1 H), 3.44-3.42(m, 1 H), 3.33-3.27 (m, 2 H), 2.35 (s, 3 H), 1.39 (s, 9 H), 1.20-1.09(m, 2 H), 0.82-0.52 (m, 6 H)

INVENTIVE EXAMPLE 17

A mixture consisting of5-amino-1-cyclopropyl-6,7-difluoro-1,14-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid (0.20 g, 0.680 mmol),(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane (0.43 g, 2.03mmol) and dimethyl sulfoxide (1.6 ml) was heated at an outer temperatureof 80° C. for 7 hours under a condition of 2.94×10⁸ Pa. When analysiswas carried out by a high performance liquid chromatography aftercompletion of the reaction, formed ratio of the compound of interest5-amino-7-[(7S)-7-tert-butoxycarbonylamino-5-azaspiro[2.4]hept-5-yl]-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylicacid was 35%. Also, residual ratio of the starting material was 63%.

¹H-NMR (DMSO-d₆) δ: 8.62 (s, 1 H), 7.20 (s, 1 H), 7.18 (s, 2 H),4.17-4.14 (m, 1 H), 3.90-3.88 (m, 2 H), 3.71-3.68 (m, 1 H), 3.44-3.42(m, 1 H), 3.33-3.27 (m, 2 H), 2.35 (s, 3 H), 1.39 (s, 9 H), 1.20-1.09(m, 2 H), 0.82-0.52 (m, 6 H)

REFERENCE EXAMPLES

The compounds (3) and (5) are well known or can be produced easily inaccordance with known methods (e.g., JP-A-2-231475, JP-A-8-277284,JP-A-9-67368, WO 97/19072, WO 97/40037, WO 98/02431, WO 98/13370 and WO98/18783). In addition, some of the compounds are synthesized by themethods shown in Reference Examples, though not limited thereto.

REFERENCE EXAMPLE 1

REFERENCE EXAMPLE 1-1

N-Methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxamide

Oxalyl chloride (6.54 ml, 0.075 mol) and dimethylformamide (3 drops)were added to ice-cooled dichloromethane solution (200 ml) of1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxylic acid (11.66 g,0.05 mol), and the mixture was stirred overnight at room temperature.After evaporation of the solvent under a reduced pressure, toluene (100ml) was added and the solvent was again evaporated under a reducedpressure. Dichloromethane (200 ml) and N,O-methylhydroxylaminehydrochloride (5.47 g, 0.055 mol) were added to the resulting residueand, while ice-cooling and stirring, dichloromethane solution (50 ml) oftriethylamine (17.4 ml, 0.125 mol) was added dropwise thereto in 15minutes. After 30 minutes of stirring under ice-cooling, this wasstirred at room temperature for 3 hours. The reaction solution waswashed with 10% citric acid aqueous solution (100 ml), water (100 ml)and saturated sodium bicarbonate aqueous solution (100 ml) in thatorder, and then dried over anhydrous sodium sulfate. The solvent wasevaporated under a reduced pressure and the residue was subjected to asilica gel column chromatography. By eluting with a chloroform:methanolof from (50:1) to (20:1), 11.32 g (82%) of the title compound wasobtained as a brown oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.54 (3 H, d, J=6.84 Hz), 2.65 (1 H, dd,J=9.77, 7.09 Hz), 2.77 (1 H, dd, J=8.79, 7.09 Hz), 3.12-3.18 (1 H, m),3.20 (3 H, s), 3.37-3.48 (1 H, m), 3.55-3.64 (1 H, m), 3.65 (3 H, s),5.50 (1 H, q, J=6.84 Hz), 7.28-7.37 (5 H, m).

REFERENCE EXAMPLE 1-2

4-(R)-Phenylcarbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

In an atmosphere of nitrogen, phenylmagnesium bromide (3 N diethyl ethersolution, 15 ml) was added dropwise to tetrahydrofuran solution (50 ml)ofN-methyl-N-methoxy-1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxamide(2.49 g, 9.0 mmol), and the mixture was stirred at room temperature for30 minutes. The reaction solution was mixed with 1 N hydrochloric acid(50 ml) under ice-cooling and extracted with ethyl acetate (8 ml×2). Theorganic layer was washed with saturated brine (100 ml) and dried overanhydrous sodium sulfate. The solvent was evaporated under a reducedpressure and the residue was subjected to a silica gel columnchromatography. By eluting with n-hexane:ethyl acetate (1:1), 2.36 g(89%) of the title compound was obtained as a light yellow oil.

¹H-NMR (400 MHz, CDCl₃) δ: 1.55 (3 H, d, J=6.83 Hz), 2.79 (1 H, dd,J=17.09, 9.77 Hz), 2.81 (1 H, dd, J=17.09, 7.81 Hz), 3.23 (1 H, dd,J=9.76, 8.79 Hz), 3.71 (1 H, dd, J=9.76, 6.35 Hz), 3.97-4.05 (1 H, m),5.54 (1 H, q, J=6.83 Hz), 7.27-7.38 (5 H, m), 7.42-7.50 (2 H, m),7.55-7.61 (1 H, m), 7.88-7.90 (2 H, m).

REFERENCE EXAMPLE 1-3

4-(R)-[1-Hydroxy-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone[F1], [F2]

Sodium borohydride (280 mg) was added to ice-cooled anhydrous ethanol(40 ml) solution of4-(R)-phenylcarbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2.17 g, 7.40mmol), and the mixture was stirred at the same temperature for 1 hour.Under ice-cooling, 10% citric acid (50 ml) was added to the reactionsolution and ethanol was evaporated under a reduced pressure. Theresidue was extracted with chloroform (80 ml×2), and the organic layerwas washed with saturated brine (100 ml) and then dried over anhydroussodium sulfate. The solvent was evaporated under a reduced pressure andthe residue was subjected to a silica gel column chromatography. Byeluting with n-hexane:ethyl acetate (1:3) to ethyl acetate (100%), 892mg (41%) of the low polarity title compound [F1] and then 1.163 g (53%)of the high polarity title compound [F2] were obtained each as a lightyellow oil.

[F1]; ¹H-NMR (400 MHz, CDCl₃) δ: 1.46 (3 H, d, J=6.84 Hz), 2.03-2.14 (2H, m), 2.44-2.54 (1 H, m), 3.05-3.09 (1 H, m), 3.36-3.40 (1 H, m), 3.47(1 H, brs), 4.45 (1 H, d, J=7.81 Hz), 5.38 (1 H, q, J=6.8 Hz), 7.22-7.31(10 H, m).

[F2]; ¹H-NMR (400 MHz, CDCl₃) δ: 1.37 (3 H, d, J=7.32 Hz), 2.26-2.32 (1H, m), 2.40-2.55 (2 H, m), 2.73-2.77 (1 H, m), 3.00-3.04 (1 H, m), 4.32(1 H, brs), 4.42 (1 H d, J=6.8 Hz), 5.33 (1 H, q, J=7.32 Hz), 7.15-7.27(10 H, m).

REFERENCE EXAMPLE 1-4

4-(R)-[1-Azido-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1],[F2]

Under ice-cooling, triethylamine (0.46 ml) and methanesulfonyl chloride(217 μl, 2.80 mmol) were added to dichloromethane (10 ml) solution of4-(R)-[1-hydroxy-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone[F1] (738 mg, 2.50 mmol), and the mixture was stirred at the sametemperature for 1 hour. Under ice-cooling, the reaction solution wasmixed with 10% citric acid (20 ml) and extracted with chloroform (30ml×2). The organic layer was washed with saturated brine (100 ml) andthen dried over anhydrous sodium sulfate. The solvent was evaporatedunder a reduced pressure, and the residue was dissolved inN,N-dimethylformamide (10 ml), mixed with sodium azide (488 mg, 7.50mmol) and then heated at 60° C. for 1.5 hours. After cooling, thereaction solution was mixed with water (50 ml) and extracted with ethylacetate (70 ml×3). The organic layer was washed with saturated brine(150 ml) and dried over anhydrous sodium sulfate. The solvent wasevaporated under a reduced pressure and the residue was subjected to asilica gel column chromatography. By eluting with n-hexane:ethyl acetate(3:2), 701 mg (87%) of the title compound was obtained as a colorlessoil.

The same reaction was also carried out on4-(R)-[1-hydroxy-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone[F2] (77%).

[F1]; ¹H-NMR (400 MHz, CDCl₃) δ: 1.46 (3 H, d, J=7.32 Hz), 2.53-2.66 (3H, m), 2.82 (1 H, dd, J=9.76, 7.81 Hz), 2.94 (1 H, dd, J=9.76, 5.86 Hz),4.37 (1 H, d, J=7.81 Hz), 5.47 (1 H, q, J=7.32 Hz), 7.21-7.42 (10 H, m).

[F2]; ¹H-NMR (400 MHz, CDCl₃) δ: 1.54 (3 H, d, J=7.33 Hz), 2.14 (1 H,dd, J=17.09, 7.81 Hz), 2.26 (1 H, dd, J=17.09, 8.78 Hz), 2.55-2.65 (1 H,m), 3.14 (1 H, dd, J=10.26, 7.81 Hz), 3.32 (1 H, dd, J=10.26, 6.34 Hz),4.36 (1 H, d, J=9.28 Hz), 5.49 (1 H, q, J=7.33 Hz), 7.26-7.43 (10 H, m).

REFERENCE EXAMPLE 1-5

4-(R)-[1-tert-Butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone[F1], [F2]

Ethanol (30 ml) solution of4-(R)-[1-azido-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F1](641 mg, 2.0 mmol) was mixed with 10% palladium-carbon catalyst (53.8%moisture, 600 mg) to carry out 6 hours of catalytic hydrogenation atroom temperature under ordinary pressure. The reaction solution wasfiltered, and the solvent was evaporated under a reduced pressure. Theresidue was dissolved in dichloromethane (20 ml), mixed withdi-tert-butyl dicarbonate (655 mg) and triethylamine (560 μl) andstirred at room temperature for 13 hours. The reaction solution wasmixed with chloroform (50 ml) and washed with 10% citric acid (8 ml) andwater (8 ml), and the organic layer was dried over anhydrous sodiumsulfate. The solvent was evaporated under a reduced pressure and theresidue was subjected to a silica gel column chromatography. By elutingwith an n-hexane:ethyl acetate system of from (1:1) to (2:3), 629 mg(80%) of the title compound was obtained as colorless crystals.

4-(R)-[1-Azido-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone [F2]was also subjected to the same reaction (76%).

[F1]; ¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (9 H, s), 1.46 (3 H, d, J=7.32Hz), 2.47-2.76 (3 H, m), 2.76-2.89 (1 H, m), 2.95-3.08 (1 H, m),4.62-4.73 (1 H, m), 4.99-5.11 (1 H, m), 5.47 (1 H, q, J=7.32 Hz),7.20-7.34 (10 H, m).

[F2]; ¹H-NMR (400 MHz, CDCl₃) δ: 1.37 (9 H, s), 1.51 (3 H, d, J=7.32Hz), 2.08-2.26 (2 H, m), 2.52-2.65 (1 H, m), 3.06-3.18 (1 H, m),3.24-3.32 (1 H, m), 4.52-4.66 (1 H, m), 5.01-5.11 (1 H, m), 5.47 (1 H,q, J=7.32 Hz), 7.19-7.35 (10 H, m).

REFERENCE EXAMPLE 1-6

3-(R)-[1-tert-Butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]pyrrolidine[F1]

In an atmosphere of nitrogen and under ice-cooling, 1 Mborane-tetrahydrofuran complex (4.6 ml) was added dropwise totetrahydrofuran solution (10 ml) of4-(R)-[1-tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone[α](600 mg, 1.52 mmol), and the mixture was stirred at room temperaturefor 13 hours. After evaporation of the solvent under a reduced pressure,the residue was mixed with 80% aqueous ethanol (15 ml) and triethylamine(3 ml), and heated under reflux for 5 hours. After spontaneous cooling,the solvent was evaporated under a reduced pressure and chloroform (30ml) was added to the residue. This was washed with water (10 ml) andsaturated brine (10 ml), and dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure and the residue wassubjected to a silica gel column chromatography. By eluting withchloroform:methanol (20:1), 510 mg (88%) of the title compound wasobtained as colorless crystals.

4-(R)-[1-tert-Butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]-2-pyrrolidone[F2] was also subjected to the same reaction (86%).

[F1]; ¹H-NMR (400 MHz, CDCl₃) δ: 1.34 (3 H, d, J=6.35 Hz), 1.47 (9 H,s), 1.60-1.78 (2 H, m), 2.18-2.39 (3 H, m), 2.42-2.54 (1 H, m),2.83-2.95 (1 H, m), 3.11 (1 H, q, J=6.35 Hz), 4.47-4.57 (1 H, m),6.06-6.18 (1 H, m), 7.16-7.33 (10 H, m).

[F2]; ¹H-NMR (400 MHz, CDCl₃) δ: 1.41 (3 H, d, J=6.35 Hz), 1.46 (9 H,s), 1.67-1.78 (1 H, m), 1.89-2.02 (1 H, m), 2.04-2.17 (1 H, m),2.17-2.28 (1 H, m), 2.37-2.50 (2 H, m), 3.01-3.19 (2 H, m), 4.48-4.58 (1H, m), 6.62-6.73 (1 H, m), 7.07-7.34 (10 H, m).

REFERENCE EXAMPLE 1-7

3-(R)-[1-tert-Butoxycarbonylamino-1-phenylmethyl]pyrrolidine [F1]

Ethanol (20 ml) solution of3-(R)-[1-tert-butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]pyrrolidine[F1] (495 mg, 1.30mmol) was mixed with 10% palladium-carbon catalyst(53.8% moisture, 500 mg), and 4 hours of catalytic hydrogenation wascarried out under atmospheric pressure while heating at an outertemperature of 50° C. The reaction solution was filtered and the solventwas evaporated under a reduced pressure to obtain 359 mg (quantitative)of crude product of the title compound as colorless crystals.

3-(R)-[1-tert-Butoxycarbonylamino-1-phenylmethyl]-1-[1-(R)-phenylethyl]pyrrolidine[F2] was also subjected to the same reaction (quantitative).

REFERENCE EXAMPLE 2

REFERENCE EXAMPLE 2-1

1-Cyclopropyl-2-propen-1-one

Under a stream of nitrogen, cyclopropyl methyl ketone (6.33 g, 75.2mmol) was dissolved in anhydrous tetrahydrofuran (75 ml). Underice-cooling and stirring, to this was added dropwise a solution preparedby dissolving N-methylanilinium trifluoroacetate (25.0 g, 113 mmol) in37% formaldehyde aqueous solution (10.2 ml) under ice-cooling. After thedropwise addition, the reaction solution was heated under reflux for 7hours. After spontaneous cooling, diethyl ether (100 ml) was added tothe reaction solution and stirred, and then the organic layer wasseparated and collected. The aqueous layer was extracted with diethylether (50 ml). Under ice-cooling, saturated sodium bicarbonate aqueoussolution (100 ml) was gradually added to the combined organic layer andstirred, and then the organic layer was separated and collected. Thethus collected organic layer was washed with saturated brine (100 ml).This was dried over anhydrous magnesium sulfate and then filtered, andthe filtrate was concentrated under a reduced pressure of 150 mmHg toobtain a yellow oil containing the title compound. This product was usedin the next reaction without purification.

¹H-NMR (400 MHz, CDCl₃) δ: 0.90-0.96 (2 H, m), 1.08-1.13 (2 H, m),2.14-2.25 (1 H, m), 5.82 (1 H, dd, J=10.74, 1.47 Hz), 6.29 (1 H, dd,J=17.57, 1.47 Hz), 6.47 (1 H, dd, J=17.57, 10.74 Hz)

REFERENCE EXAMPLE 2-2

Cyclopropyl[1-[1-(R)-phenylethyl]pyrrolidin-3-yl]ketone

The product (8.01 g) containing 1-cyclopropyl-2-propen-1-one describedin Reference Example 1 andN-(n-butoxymethyl)-N-[1-(R)-phenylethyl]trimethylsilylmethylamine (23.2g, 79.9 mmol) were dissolved in dry dichloroethane (350 ml), andtrifluoroacetic acid (500 μl) was added dropwise thereto. After 12 hoursof stirring at room temperature, the reaction solution was washed withsaturated sodium bicarbonate aqueous solution (100 ml) and then withsaturated brine (100 ml). After drying over anhydrous magnesium sulfateand subsequent filtration, the filtrate was concentrated under a reducedpressure. The thus obtained residue was subjected to a flash silica gelchromatography, and 9.08 g (49.6%) of the title compound was obtainedfrom an eluate of n-hexane:ethyl acetate=2:1 as a colorless oilcomponent. In this case, this product was obtained as a diastereomermixture of 1:1.

¹H-NMR (400 MHz, CDCl₃) δ: 0.83-0.88 (2 H, m), 0.99-1.02 (2 H, m), 1.38(3 H×½, d, J=2.93 Hz), 1.40 (3H×½, d, J=2.44 Hz), 1.62-1.76 (1 H, m),1.90-2.17 (2 H, m), 2.35-2.93 (4 H, m), 3.22-3.26 (2 H, m), 7.23-7.34 (5H, m)

REFERENCE EXAMPLE 2-3

3-[1-(tert-Butoxycarbonyl)amino-1-cyclopropyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine

Cyclopropyl[1-[1-(R)-phenylethyl]pyrrolidin-3-yl]ketone (1.563 g, 7.793mmol) was dissolved in anhydrous methanol (25 ml). To this were addedammonium acetate (5.236 g, 67.93 mmol), sodium cyanoborohydride (435.2mg, 6.925 mmol) and Molecular Sieves 4A powder (1.86 g), and the mixturewas stirred at room temperature for 16 hours under a stream of nitrogen.The reaction solution was filtered through celite and then the solventwas evaporated under a reduced pressure. The residue was dissolved indichloromethane (100 ml), washed with saturated sodium bicarbonateaqueous solution (50 ml) and saturated brine (50 ml) in that order, andthen dried over anhydrous magnesium sulfate. After filtration, thesolvent was evaporated under a reduced pressure. The thus obtainedresidue was dissolved in dry dichloromethane (25 ml) to which, underice-cooling, was subsequently added dropwise dichloromethane (5 ml)solution of di-tert-butyl dicarbonate (2.225 g, 10.19 mmol). Thereaction solution was stirred at room temperature for 2 hours and thenconcentrated under a reduced pressure. The thus obtained residue wassubjected to a flash silica gel chromatography, and 1.299 g (55.5%) ofthe title compound was obtained from an eluate ofchloroform:methanol=10:1 as a colorless oil component.

¹H-NMR (400 MHz, CDCl₃) δ: 0.20-0.30, 0.35-0.52, 0.68-0.78 (4 H, m),1.36 (3 H×¼, d, J=5.86 Hz), 1.39 (3H×¾, d, J=5.86 Hz), 1.43 (9 H×¼, s),1.45 (9 H×¾, s), 1.61-1.74 (1 H, m), 2.25-2.76, 2.80-3.07, 3.18-3.26 (9H, m), 5.28 (1 H, brs), 7.23-7.34 (5 H, m)

REFERENCE EXAMPLE 2-4

1-Benzyloxycarbonyl-3-[1-(tert-butoxycarbonyl)amino-1-cyclopropyl]methylpyrrolidine(F1, F2, F3, F4)

3-[1-(tert-Butoxycarbonyl)amino-1-cyclopropyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine(1.234 g, 3.582 mmol) was dissolved in dry dichloromethane (20 ml) towhich, under ice cooling, was subsequently added dropwise benzylchloroformate (1,278 μl, 8.955 mmol). After 8 hours of stirring at roomtemperature, the reaction solution was concentrated under a reducedpressure. The thus obtained residue was subjected to a flash silica gelchromatography, and 959 mg (71.5%) of the title compound was obtainedfrom an eluate of n-hexane:ethyl acetate=2:1 as a colorless oilcomponent.

Next, this product was applied to a fractional HPLC using a chiralcolumn, and four optical isomers F1, F2, F3 and F4 were separated andpurified.

HPLC Fractionation Conditions;

Column: CHIRALPAKAD (Daicel Chemical Industries), 2 cm×25 cm

Mobile phase: n-hexane:2-propanol=80:20 (v/v)

Flow rate: 5.0 ml/min

Temperature: room temperature

Detection: UV (254 nm)

Retention Time of Each Isomer

F1: 18 minutes; F2: 23 minutes; F3: 26 minutes; F4: 30 minutes

Isomer F1: Colorless Amorphous, 229 mg (17.0%);

¹H-NMR (400 MHz, CDCl₃) δ: 0.27-0.32 (2 H, m), 0.41-0.45 (1 H, m),0.54-0.61 (1 H, m), 0.72-0.79 (1 H, m), 1.43 (9 H, s), 1.66-1.78 (1 H,m), 1.99-2.08 (1 H, m), 2.30-2.36 (1 H, m), 2.90-3.03 (1 H, m),3.12-3.26 (1 H, m), 3.28-3.36 (1 H, m), 3.49-3.72 (2 H, m), 4.50 (1 H,brs), 5.13 (2 H, s), 7.30-7.37 (5 H, m)

Isomer F2: Colorless Amorphous, 96 mg (7.2%);

¹H-NMR (400 MHz, CDCl₃) δ: 0.29-0.37 (2 H, m), 0.40-0.45 (1 H, m),0.57-0.62 (1 H, m), 0.76-0.79 (1 H, m), 1.43 (9 H, s), 1.68-1.78 (1 H,m), 2.04-2.09 (1 H, m), 2.36-2.40 (1 H, m), 2.95-3.09 (1 H, m), 3.16 (1H, t, J=10.74 Hz), 3.31-3.39 (1 H, m), 3.54-3.68 (2 H, m), 4.47 (1 H,brs), 5.13 (2 H, s), 7.29-7.37 (5 H, m)

Isomer F3: Colorless Amorphous, 140 mg (10.4%);

¹H-NMR (400 MHz, CDCl₃) δ: 0.27-0.39 (2 H, m), 0.41-0.45 (1 H, m),0.54-0.62 (1 H, m), 0.72-0.80 (1 H, m), 1.43 (9 H, s), 1.66-1.79 (1 H,m), 2.04-2.09 (1 H, m), 2.37-2.40 (1 H, m), 2.95-3.08 (1 H, m), 3.16 (1H, t, J=10.74 Hz), 3.32-3.39 (1 H, m), 3.54-3.68 (2 H, m), 4.48 (1 H,brs), 5.13 (2 H, s), 7.30-7.37 (5 H, m)

Isomer F4: Colorless Amorphous, 296 mg (22.1%);

¹H-NMR (400 MHz, CDCl₃) δ: 0.27-0.33 (2 H, m), 0.41-0.45 (1 H, m),0.54-0.62 (1 H, m), 0.72-0.80 (1 H, m), 1.43 (9 H, s), 1.68-1.78 (1 H,m), 1.99-2.09 (1 H, m), 2.29-2.39 (1 H, m), 2.90-3.03 (1 H, m),3.12-3.26 (1 H, m), 3.28-3.37 (1 H, m), 3.49-3.73 (2 H, m), 4.50 (1 H,brs), 5.13 (2 H, s), 7.30-7.37 (5 H, m)

Based on the result of the analysis of these ¹H-NMR data, it wasrevealed that each of F1 and F4, and F2 and F3, among these four opticalisomers has an enantiomer relationship.

REFERENCE EXAMPLE 3

REFERENCE EXAMPLE 3-1

1-[1-(R)-Phenylethyl]-5-oxopyrrolidine-3-(R)—(N-methyl-N-methoxy)carboxamide

Under ice-cooling, oxalyl chloride (6.54 ml, 75.0 mmol) anddimethylformamide (3 drops) were added to dichloromethane solution (200ml) of 1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-carboxylic acid(11.7 g, 50.0 mmol), and the mixture was stirred at room temperature fora whole day and night. After evaporation of the solvent under a reducedpressure, toluene (100 ml) was added and the solvent was againevaporated under a reduced pressure. Dichloromethane (200 ml) andN,O-methylhydroxylamine hydrochloride (5.47 g, 55.5 mmol) were added tothe resulting residue and, while ice-cooling and stirring,dichloromethane solution (50 ml) of triethylamine (17.4 ml, 125 mmol)was added dropwise thereto spending 15 minutes. After stirring underice-cooling for 30 minutes, this was further stirred at room temperaturefor 3 hours. The reaction solution was washed with 10% citric acidaqueous solution (100 ml), water (100 ml) and saturated sodiumbicarbonate aqueous solution (100 ml) in that order, and then dried overanhydrous sodium sulfate. The solvent was evaporated under a reducedpressure and the residue was subjected to a silica gel columnchromatography to obtain 11.3 g (82%) of the title compound as a brownoil from an eluate of chloroform:methanol=50:1 to 20:1.

¹H-NMR (400 MHz, CDCl₃) δ: 1.54 (3 H, d, J=6.84 Hz), 2.65 (1 H, dd,J=9.77, 7.09 Hz), 2.77 (1 H, dd, J=8.79, 7.09 Hz), 3.12-3.18 (1 H, m),3.20 (3 H, s), 3.37-3.48 (1 H, m), 3.55-3.64 (1 H, m), 3.65 (3 H, s),5.50 (1 H, q, J=6.84 Hz), 7.28-7.37 (5 H, m).

REFERENCE EXAMPLE 3-2

4-(R)-Cyclobutylcarbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

In an atmosphere of nitrogen, cyclobutylmagnesium chloride (1 Ntetrahydrofuran solution, 28 ml) prepared from chlorocyclobutane wasadded dropwise to tetrahydrofuran solution (50 ml) of1-[1-(R)-phenylethyl]-5-oxopyrrolidine-3-(R)-(N-methyl-N-methoxy)carboxamide (1.93 g, 7.00 mmol), and the mixture was stirred at roomtemperature for 30 minutes. The reaction solution was mixed with 1 Nhydrochloric acid (50 ml) under ice-cooling and then extracted withethyl acetate (80 ml×2). The organic layer was washed with saturatedbrine (100 ml) and dried over anhydrous sodium sulfate. The solvent wasevaporated under a reduced pressure and the residue was subjected to asilica gel column chromatography to obtain 1.47 g (78%) of the titlecompound as a light yellow oil from an eluate of n-hexane:ethylacetate=1:2.

¹H-NMR (400 MHz, CDCl₃) δ: 1.53 (3 H, d, J=7.33 Hz), 1.78-1.89 (1 H, m),1.92-2.06 (1 H, m), 2.06-2.31 (4 H, m), 2.58-2.65 (2 H, m), 3.05 (1 H,dd, J=9.28, 8.79 Hz), 3.13-3.21 (1 H, m), 3.31 (1 H, quint, J=8.30),3.53 (1 H, dd, J=9.28, 6.83 Hz), 5.48 (1 H, q, J=7.33 Hz), 7.27-7.37 (5H, m).

REFERENCE EXAMPLE 3-3

4-(R)-(1-Cyclobutyl-1-hydroxy)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

Under ice-cooling, sodium borohydride (295 mg) was added to ethanol (40ml) solution of4-(R)-cyclobutylcarbonyl-1-[1-(R)-phenylethyl]-2-pyrrolidone (2.12 g,7.80 mmol), and the mixture was stirred at the same temperature for 1hour. 10% Citric acid (50 ml) was added to the reaction solution underice-cooling, ethanol was evaporated under a reduced pressure, theresidue was extracted with chloroform (80 ml×2), and the organic layerwas washed with saturated brine (100 ml) and then dried over anhydroussodium sulfate. The solvent was evaporated under a reduced pressure andthe resulting residue was subjected to a silica gel columnchromatography to obtain 2.10 g (98%) of the title compound as a lightyellow oil (isomer mixture) from an eluate of n-hexane:ethylacetate=1:3.

¹H-NMR (400 MHz, CDCl₃) δ: 1.50 (3 H, d, J=6.83 Hz), 1.68-2.01 (6 H, m),2.14-2.45 (3 H, m), 2.45-2.56 (1 H, m), 2.91-3.05 (1 H, m), 3.19-3.31 (1H, m), 3.41-3.49 (1 H, m), 5.42-5.49 (1 H, m), 7.24-7.36 (5 H, m).

REFERENCE EXAMPLE 3-4

4-(R)-(1-Azido-1-cyclobutyl)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone

Under ice-cooling, triethylamine (1.36 ml, 9.80 mmol) andmethanesulfonyl chloride (640 μl, 8.30 mmol) were added in that order todichloromethane (35 ml) solution of4-(R)-(1-cyclobutyl-1-hydroxy)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone(2.05 g, 7.50 mmol), and the mixture was stirred at the same temperaturefor 1 hour. The reaction solution was mixed with 10% citric acid (35 ml)under ice-cooling, and extracted with chloroform (50 ml×2), and theorganic layer was washed with saturated brine (150 ml) and then driedover anhydrous sodium sulfate. The solvent was evaporated under areduced pressure, and the residue was dissolved inN,N′-dimethylformamide (30 ml), mixed with sodium azide (1.46 g, 22.5mmol) and then stirred at 60° C. for 3 hours. After spontaneous cooling,the reaction solution was mixed with water (150 ml) and extracted withethyl acetate (150 ml×3), and the organic layer was washed withsaturated brine (150 ml) and dried over anhydrous sodium sulfate. Thesolvent was evaporated under a reduced pressure and the residue wassubjected to a silica gel column chromatography to obtain 898 mg (40%)of the low polarity title compound (isomer B1) as a colorless oil froman eluate of n-hexane:ethyl acetate=3:2 and also 847 mg (38%) of thehigh polarity title compound (isomer B2) as colorless crystals from aneluate of n-hexane:ethyl acetate=2:3.

Isomer B1: ¹H-NMR (400 MHz, CDCl₃) δ: 1.52 (3 H, d, J=6.83 Hz),1.72-2.01 (5 H, m), 2.07-2.17 (1 H, m), 2.26-2.41 (3 H, m), 2.45-2.56 (1H, m), 2.98 (1 H, dd, J=9.77, 7.81 Hz), 3.14 (1 H, dd, J=9.77, 7.32 Hz),3.32 (1 H, dd, J=8.76, 3.91 Hz), 5.47 (1 H, q, J=6.83 Hz), 7.25-7.35 (5H, m).

Isomer B2: ¹H-NMR (400 MHz, CDCl₃) δ: 1.52 (3 H, d, J=6.83 Hz),1.75-2.03 (5 H, m), 2.03-2.17 (1 H, m), 2.19-2.38 (2 H, m), 2.40-2.56 (2H, m), 2 H, m), 2.99 (1 H, dd, J=9.77, 8.30 Hz), 3.14 (1 H, dd, J=9.77,7.32 Hz), 3.30 (1 H, dd, J=8.30, 6.34 Hz), 5.47 (1 H, q, J=6.83 Hz),7.25-7.35 (5 H, m).

REFERENCE EXAMPLE 3-5

4-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone(Isomer B1)

Ethanol (50 ml) solution of4-(R)-(1-azido-1-cyclobutyl)methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone(isomer B1) (835 mg, 2.80 mmol) was mixed with 10% palladium-carboncatalyst (53.8% moisture, 850 mg) to carry out 5 hours of catalytichydrogenation in an atmosphere of hydrogen at room temperature underatmospheric pressure. The reaction solution was filtered, and thesolvent was evaporated under a reduced pressure. The thus obtainedresidue was dissolved in dichloromethane (20 ml), mixed withdi-tert-butyl dicarbonate (917 mg) and triethylamine (780 μl), andstirred at room temperature for 15 hours. The reaction solution wasmixed with chloroform (50 ml) and washed with 10% citric acid (80 ml)and water (80 ml), and the organic layer was dried over anhydrous sodiumsulfate. The solvent was evaporated under a reduced pressure and theresidue was subjected to a silica gel column chromatography to obtain809 mg (78%) of the title compound as a white amorphous from an eluateof n-hexane:ethyl acetate=3:2 to 1:1.

¹H-NMR (400 MHz, CDCl₃) δ: 1.44 (9 H, s), 1.48 (3 H, d, J=7.32 Hz),1.66-1.98 (6 H, m), 2.17-2.43 (4 H, m), 2.94-3.03 (1 H, m), 3.09-3.18 (1H, m), 3.59-3.68 (1 H, m), 4.46-4.58 (1 H, m), 5.46 (1 H, q, J=7.32 Hz),7.27-7.35 (5 H, m).

REFERENCE EXAMPLE 3-6

3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidine(Isomer B1)

In an atmosphere of nitrogen and under ice-cooling, 1 Mborane-tetrahydrofuran complex solution (5.6 ml) was added dropwise totetrahydrofuran solution (15 ml) of4-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]-2-pyrrolidone(isomer B1) (700 mg, 1.88 mmol), and the mixture was stirred at roomtemperature for 13 hours. After evaporation of the solvent under areduced pressure, the residue was mixed with 80% aqueous ethanol (15 ml)and triethylamine (3 ml), and heated under reflux for 4 hours. Afterspontaneous cooling, the solvent was evaporated under a reducedpressure, and the thus obtained residue was mixed with chloroform (30ml), washed with water (10 ml) and saturated brine (10 ml), and thendried over anhydrous sodium sulfate. The solvent was evaporated under areduced pressure and the resulting residue was subjected to a silica gelcolumn chromatography to obtain 565 mg (84%) of the title compound ascolorless crystals from an eluate of chloroform:methanol=20:1.

¹H-NMR (400 MHz, CDCl₃) δ: 1.36 (3 H, d, J=6.84 Hz), 1.45 (9 H, s),1.66-1.95 (7 H, m), 2.05-2.22 (2 H, m), 2.22-2.34 (1 H, m), 2.34-2.45 (2H, m), 3.15 (1 H, q, J=6.84 Hz), 3.43-3.53 (1 H, m), 4.54-4.62 (1 H, m),7.21-7.31 (5 H, m).

REFERENCE EXAMPLE 3-7

3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methylpyrrolidine(Isomer B1)

Ethanol (30 ml) solution of3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine(isomer B1) (516 mg, 1.44 mmol) was mixed with 10% palladium-carboncatalyst (53.8% moisture, 500 mg), and 5 hours of catalytichydrogenation was carried out in an atmosphere of hydrogen at an outertemperature of 50° C. under atmospheric pressure. The reaction solutionwas filtered and the solvent was evaporated under a reduced pressure toobtain 366 mg (quantitative) of the title compound as colorlesscrystals.

REFERENCE EXAMPLE 4

6-Fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-7-(4-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylicacid

1-Methylpiperazine (1.55 ml, 14.0 mmol) and triethylamine (1.95 ml, 14mmol) were added to dry dimethyl sulfoxide (18 ml). Thereto was added6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid-BF₂chelate (3.61 g, 10.0 mmol), and the mixture was stirred at roomtemperature for 22 hours. After concentration of the reaction solutionunder a reduced pressure, the residue was suspended in a solution ofethanol:water=9:1 (110 ml), mixed with triethylamine (2 ml) and thenheated under reflux for 2 hours. After cooling, the reaction solutionwas concentrated under a reduced pressure. Concentrated hydrochloricacid (20 ml) was added dropwise to the residue under ice-cooling, andthe mixture was stirred at room temperature for 30 minutes. The reactionsolution was mixed with 1 N hydrochloric acid (5 ml), and the resultingyellow and acidic aqueous solution was washed with chloroform (50 ml×4)and then adjusted to pH 12.0 with sodium hydroxide aqueous solution. Thebasic aqueous solution was adjusted to pH 7.4 with 1 N hydrochloric acidand then extracted with chloroform (150 ml×5). After drying withanhydrous sodium sulfate, the solvent was evaporated under a reducedpressure. By recrystallizing and purifying the resulting residue fromisopropyl alcohol, 2.98 g (7.58 mmol, 76%) of the title compound wasobtained as yellow crystals.

¹H-NMR (400 MHz, 0.1N NaOD) δ: 1.37-1.53 (2 H, m), 2.17 (3 H, s),2.43-2.48 (4 H, m), 3.17-3.22 (4 H, m), 3.63-3.68 (3 H, m), 3.90-3.94 (1H, m), 4.82 (1 H, dm, J=62.0 Hz), 7.59 (1 H, d, J=12.7 Hz), 8.40 (1 H,s).

IR (KBr disk): 2931, 2841, 2817, 2796, 1898, 1768, 1722, 1622, 1603,1512, 1462, 1435, 1394, 1315, 1290, 1242, 1227, 1207 cm⁻¹

Melting point; 192-194° C.

Elemental analysis data: FW 393.39 for C₁₉H₂₁F₂N₃O₄ Calcd.: C 58.01%; H5.38%; N 10.68% Found: C 58.02%; H 5.42%; N 10.41%

REFERENCE EXAMPLE 5

7-(3,5-Cis-dimethylpiperazin-1-yl)-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoguinoline-3-carboxylicacid

C is-2,6-dimethylpiperazine (1.14 g, 10.0 mmol) and triethylamine (1.05ml, 7.5 mmol) were added to dry dimethyl sulfoxide (10 ml). Thereto wasadded6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylicacid-BF₂ chelate (1.81 g, 5.00 mmol), and the mixture was stirred atroom temperature for 5 days. After concentration of the reactionsolution under a reduced pressure, the residue was suspended in asolution of ethanol:water=9:1 (50 ml), mixed with triethylamine (1 ml)and then heated under reflux for 3 hours. After cooling, the reactionsolution was concentrated under a reduced pressure. Concentratedhydrochloric acid (10 ml) was added dropwise to the residue underice-cooling, and the mixture was stirred at room temperature for 30minutes. The reaction solution was mixed with 1 N hydrochloric acid (5ml), and the resulting yellow and acidic aqueous solution was washedwith chloroform (50 ml×4) and then adjusted to pH 12.0 with sodiumhydroxide aqueous solution. The basic aqueous solution was adjusted topH 7.4 with 1 N hydrochloric acid and then extracted with chloroform(150 ml×3). After drying with anhydrous sodium sulfate, the solvent wasevaporated under a reduced pressure. By recrystallizing and purifyingthe resulting residue from ethanol, 1.27 g (3.12 mmol, 62%) of the titlecompound was obtained as yellow crystals.

¹H-NMR (400 MHz, 0.1 N NaOD) δ: 1.06 (3 H, s), 1.07 (3 H, s), 1.50-1.68(2 H, m), 2.77 (1 H, t, J=11.0 Hz), 2.87 (1 H, t, 10.0 Hz), 2.99-3.06 (2H, m), 3.28-3.35 (2 H, m), 3.75 (3 H, s), 4.02-4.07 (1 H, m), 4.97 (1 H,dm, J=64.1 Hz), 7.72 (1 H, d, J=12.7 Hz), 8.50 (1 H, s).

Melting point; 129-131° C.

Elemental analysis data: FW 425.43 for C₂₀H₂₃F₂N₃O₄.1H₂O Calcd.: C56.46%; H 5.92%; N 9.88% Found: C 56.72%; H 5.92%; N 9.85%

Industrial Applicability

Effects of the invention can be enumerated as follows.

Since the reaction according to the production method of the inventionis carried out within a shorter period of time by pressurizing in aclosed system, in comparison with the conventional methods (opensystem),

(1) the progress of side reactions (illustratively, decompositionreaction of the quinolone compound as a raw material and decompositionreaction of the solvent) is inhibited,

(2) the inhibition of decomposition of the quinolone compound as astarting material renders possible easy purification of the product ofinterest, by preventing complex reaction and progress of coloring,

(3) the inhibition of decomposition of the quinolone compound as astarting material renders possible further improvement of the yield ofthe product of interest, by more shorter period of reaction of theremaining quinolone compound, and

(4) the remaining quinolone compound as a starting material can berecovered and recycled to the reaction, so that these effects renderpossible improvement of the yield.

Accordingly, a new method for efficiently introducing an aminesubstitution as the 7-position substituent of the quinolonecarboxylicacid derivative is provided by the invention.

What is claimed is:
 1. A method for producing a compound represented byformula (2):

(wherein R¹, R², R³, R⁴, R, X¹ and Y are as defined in the following),which comprises allowing a compound represented by formula (1):

[wherein R¹ represents an alkyl group having from 1 to 6 carbon atoms,an alkenyl group having from 2 to 6 carbon atoms, a halogenoalkyl grouphaving from 1 to 6 carbon atoms, a cyclic alkyl group having from 3 to 6carbon atoms which may have a substituent, an aryl group which may havea substituent, a heteroaryl group which may have a substituent, analkoxy group having from 1 to 6 carbon atoms or an alkylamino grouphaving from 1 to 6 carbon atoms, R² represents a hydrogen atom or analkylthio group having from 1 to 6 carbon atoms, wherein R² and R¹ maybe combined to form a cyclic structure together with the carbon atom andnitrogen atom, to which they are bonded, and this ring may contain asulfur atom as a constituting atom and may further have an alkyl grouphaving from 1 to 6 carbon atoms as a substituent, R³ represents ahydrogen atom, an amino group, a thiol group, a halogenomethyl group, analkyl group having from 1 to 6 carbon atoms, an alkenyl group havingfrom 2 to 6 carbon atoms, an alkynyl group having from 2 to 6 carbonatoms or an alkoxy group having from 1 to 6 carbon atoms, wherein theamino group may have one or more substituents selected from the groupconsisting of a formyl group, an alkyl group having from 1 to 6 carbonatoms and an acyl group having from 2 to 5 carbon atoms, R⁴ represents ahydrogen atom, an amino group, a halogen atom, a cyano group, ahalogenomethyl group, a halogenomethoxy group, an alkyl group havingfrom 1 to 6 carbon atoms, an alkenyl group having from 2 to 6 carbonatoms, an alkynyl group having from 2 to 6 carbon atoms or an alkoxygroup having from 1 to 6 carbon atoms, wherein the amino group may haveone or more substituents selected from the group consisting of a formylgroup, an alkyl group having from 1 to 6 carbon atoms and an acyl grouphaving from 2 to 5 carbon atoms, and R⁴ and R¹ may be combined to form acyclic structure together with the carbon atom and nitrogen atom, towhich they are bonded, and this ring may contain an oxygen atom, anitrogen atom or a sulfur atom as a constituting atom and may furtherhave an alkyl group having from 1 to 6 carbon atoms as a substituent, X¹represents a hydrogen atom or a halogen atom, X² represents a halogenatom, and Y represents a hydrogen atom, a phenyl group, an acetoxymethylgroup, a pivaloyloxymethyl group, an ethoxycarbonyl group, a cholinegroup, a dimethylaminoethyl group, a 5-indanyl group, a phthalidynylgroup, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a3-acetoxy-2-oxobutyl group, an alkyl group having from 1 to 6 carbonatoms, an alkoxymethyl group having from 2 to 7 carbon atoms, aphenylalkyl group composed of an alkylene group having from 1 to 6carbon atoms and phenyl group, or a group of the following formula:—B(R⁵)₂ (wherein R⁵ represents a fluorine atom or an acyloxy grouphaving from 2 to 7 carbon atoms)] to react with a nitrogen-containingbasic compound represented by the following formula: R—H (wherein Rrepresents a nitrogen-containing basic substituent in which a nitrogenatom is the binding position), under a pressurized condition in a rangeof 1.5×10⁷ to 3.5×10⁸ Pa in the presence, if necessary, of a base. 2.The production method according to claim 1, wherein thenitrogen-containing basic compound (R—H) is a compound represented byformula (3):

[wherein R⁶ and R⁷ may be the same or different from each other and eachrepresents an optional substituent selected from an alkyl group havingfrom 1 to 6 carbon atoms which may be substituted by an optionalsubstituent selected from groups (halogen, C₁₋₆ alkyl group and C₁₋₆alkoxy group), an alkyl group having from 1 to 6 carbon atoms, an arylgroup having from 6 to 10 carbon atoms, an aralkyl group having from 7to 12 carbon atoms, an acyl group having from 1 to 6 carbon atoms, acycloalkyl group having from 3 to 6 carbon atoms and a hydrogen atom(wherein the cycloalkyl group, aryl group and aralkyl group may become aheterocycle containing one or more hetero-atoms selected from a nitrogenatom, an oxygen atom and a sulfur atom) or R⁶ and R⁷ may form a ringtogether with the nitrogen atom, to which they are bonded, and theformed ring is a monocyclic, bicyclic or tricyclic nitrogen-containingheterocyclic substituent group, the heterocyclic substituent group maybe either saturated or unsaturated, may further contain one or morehetero-atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom and may have a bicyclo structure or spiro cyclic structure, and theheterocyclic substituent group may be substituted by one or moreoptional substituents selected from groups (1), (2) and (3), substituentgroup (1); a C₆₋₁₀ aryl group, a heteroaryl group (five-membered ring orsix-membered ring which may contain from 1 to 4 hetero-atoms optionallyselected from N, O and S), a C₇₋₁₂ aralkyl group and a C₆₋₁₀heteroaralkyl group (which may contain from 1 to 4 hetero atomsoptionally selected from N, O and S) substituent group (2); an aminogroup, a C₁₋₆ alkyl group, a C₁₋₆ alkylamino group, a C₁₋₆ alkylthiogroup, a C₁₋₆ halogenoalkyl group and a C₁₋₆ aminoalkyl groupsubstituent group (3); a halogen atom, a hydroxyl group, a carbamoylgroup and a C.sub.1-6 alkoxyl group (the alkyl group moiety ofsubstituent group (2) may have a cyclic structure)].
 3. The productionmethod according to claim 1 or 2, wherein lower limit of the pressure is1×10⁷ Pa and upper limit of the pressure is 5×10⁸ Pa.
 4. The productionmethod according to claim 1 or 2, wherein the compound of formula (I) isa compound represented by formula (A):

[wherein X¹ represents a hydrogen atom or a halogen atom, X² representsa halogen atom, X³ represents a hydrogen atom or a halogen atom, R¹⁶represents a hydrogen atom or an acyl group, R¹⁷ represents an acylgroup, and R¹⁸ represents a hydrogen atom, an alkyl group having from 1to 6 carbon atoms or a boron-containing substituent represented by thefollowing formula: —B(R⁵)₂ (wherein R⁵ represents a halogen atom or anacyloxy group)].
 5. The production method according to claim 1 or claim2, wherein R⁵ is a halogen atom or an alkylcarbonyloxy group.
 6. Theproduction method according to claim 1 or claim 2, wherein R⁵ is afluorine atom or an acetyloxy group.
 7. The production method accordingto claim 1 or claim 2, wherein the nitrogen-containing basic compound(R—H) is a compound represented by formula (B):

[wherein each of R¹⁹ and R²⁰ independently represents a hydrogen atom, alower alkyl group or an amino-substituted cyclopropyl group (this aminogroup may have a substituent or a protective group), or R¹⁹ and R²⁰ maybe combined into a group represented by the following formula:  —(CH₂)₂—and form a spiro cyclic structure together with the pyrrolidine ring,and R²¹ represents a halogen atom or an amino group which may have asubstituent or a protective group].
 8. The production method accordingto claim 7, wherein R¹⁹ and R²⁰ are a group represented by the followingformula: —(CH₂)₂— and R²¹ is an amino group which may have a substituentor a protective group.
 9. The production method according to claim 8,wherein the amino group is an amino group of (S)-configuration.
 10. Theproduction method according to claim 7, wherein R¹⁹ is a hydrogen atom,R²⁰ is an amino-substituted cyclopropyl group (this amino group may havea substituent or a protective group) and R²¹ is a halogen atom.
 11. Theproduction method according to claim 10, wherein R²¹ is a fluorine atom.12. The production method according to claim 10, wherein R²⁰ and R²¹ arein cis-form.
 13. The production method according to claim 12, whereinR²⁰ is (R)-configuration and R²¹ is (S)-configuration.